Methods of using (+)-1,4-dihydro-7-[(3s,4s)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid for treatment of cancer

ABSTRACT

Methods of treating, preventing or managing cancer, including certain leukemias are disclosed. The methods encompass the administration of enantiomerically pure (+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid. Also provided are methods of treatment using this compound with chemotherapy, radiation therapy, hormonal therapy, biological therapy or immunotherapy. Pharmaceutical compositions and single unit dosage forms suitable for use in the methods are also disclosed.

This application claims priority to U.S. patent application Ser. Nos.11/218,387 and 11/218,653, both of which were filed Sep. 2, 2005, [andare now being converted to U.S. provisional applications,] and to U.S.Provisional Nos. 60/789,093 and 60/788,927, both filed Apr. 3, 2006 and60/810,285, filed Jun. 1, 2006. All of these applications areincorporated in their entirety by reference.

1. FIELD

Provided herein are methods for treating, preventing or managing cancer,including specific leukemias by administering enantiomerically pure(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid, which is also known as SNS-595 or AG-7352. Also provided aredoses, dosing regimens and dosages for SNS-595 and its administration.

2. BACKGROUND

SNS-595 is chemically named(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid, and has the following structure:

SNS-595 is known for its anti-tumor activity. Treatment of the followingcancers with SNS-595 has been proposed in the literature: bladdercancer, breast cancer, cervical cancer, colon cancer, esophageal cancer,head and neck cancer, liver cancer, lung cancer, melanoma, myeloma,neuroblastoma (i.e., CNS cancer), ovarian cancer, pancreatic cancer,prostate cancer, renal cancer, sarcoma, skin cancer, stomach cancer,testicular cancer, thyroid cancer and uterine cancer. Various dosingregimens have been reported, for example, see, U.S. Patent ApplicationPub. Nos. 2005-0203120; 2005-0215583 and 2006-0025437, all of which areincorporated herein by reference in their entirety.

There continues to be a need for safe and effective dosages and dosingregimens for administering SNS-595 in treating, preventing and managingvarious cancers, including leukemias.

3. SUMMARY

SNS-595 is a known cytotoxic agent with utility against various cancers.Herein are discussed novel treatment methods including the treatment ofspecific leukemias. In addition, described are unique dosing ranges,regimens and pharmaceutical doses.

The treatment, prevention or management of cancer using SNS-595,pharmaceutical compositions thereof and unique dosing is described.Generally, the types of cancers that can be treated, prevented ormanaged using methods provided herein include, but are not limited to:bladder cancer, breast cancer, cervical cancer, colon cancer (includingcolorectal cancer), esophageal cancer, head and neck cancer, livercancer, lung cancer (both small cell and non-small cell), melanoma,myeloma, neuroblastoma (i.e., CNS cancer), ovarian cancer, pancreaticcancer, prostate cancer, renal cancer, sarcoma (including osteosarcoma),skin cancer (including squamous cell carcinoma), stomach cancer,testicular cancer, thyroid cancer, and uterine cancer. The cancer can berelapsed, refractory or resistant to conventional therapy.

In certain embodiments, the cancer includes hematologic malignancies,including, but not limited to leukemias, lymphomas (Non-Hodgkin'sLymphoma), Hodgkin's disease (also called Hodgkin's Lymphoma) andmyeloma. The various forms of leukemias include, but are not limited to,chronic lymphocytic leukemia, chronic myeloid leukemia, acutelymphocytic leukemia, acute myelogenous leukemia and acute myeloblasticleukemia. The leukemia can be relapsed, refractory or resistant. Incertain embodiments, the hematologic malignancy is promyelocyticleukemia, T-cell leukemia or lymphoblastic leukemia.

Further provided are methods of treating, preventing or managing cancerby administering SNS-595 in a certain manner. In certain embodiment, themethods comprise administering to a mammal a dose of about 1 mg/m² to150 mg/m², about 1 mg/m² to 100 mg/m², 1 mg/m² to 75 mg/m², 15 mg/m² to80 mg/m², or about 3 mg/m² to 24 mg/m² of SNS-595, on the basis of bodysurface area. In certain embodiment, the methods comprise administeringto a mammal a dose of about 15 g/m², 25 g/m² or 50 mg/m² of SNS-595, onthe basis of body surface area. Additional dosing and dosing regimensare described in more detail herein below.

Also provided herein are dosing and dosing regimens for solid cancers.The administered dose of SNS-595 can be delivered as a single dose suchas, for example, an IV push of 10-15 minutes duration (e.g., a singlebolus injection) or over time such as, for example, a 24-hour period(e.g., continuous infusion over time or divided bolus doses over time)and is repeated as necessary, for example, until the patient experiencesstable disease or regression, or until the patient experiences diseaseprogression or unacceptable toxicity.

In some embodiments, SNS-595 can be cyclically administered to apatient. Cycling therapy involves the administration of the active agentfor a period of time, followed by a rest for a period of time andrepeating this sequential administration. Cycling therapy can reduce thedevelopment of resistance to one or more of the therapies, avoid orreduce the side effects of one of the therapies and/or improves theefficacy of the treatment.

In another embodiment, SNS-595 is administered in combination withanother drug (“second active agent”) or another therapy conventionallyused to treat, prevent or manage cancer, or the methods of dosing ofSNS-595 described herein can be applied in combination therapy settings.Second active agents include known small molecule, anticancer, antitumoror cytotoxic agents and large molecules (e.g., proteins and antibodies),examples of which are provided herein, as well as stem cells or cordblood. Examples of such conventional therapies include, but are notlimited to, surgery, chemotherapy, radiation therapy, hormonal therapy,biological therapy, immunotherapy, blood transfusions, and combinationsthereof.

Thus, in certain embodiment, provided herein are combinations fortreatment, prevention and management of solid tumors. In otherembodiment, provided herein are combinations for treatment, preventionand management of leukemias and lymphomas.

Also provided are pharmaceutical compositions, single unit dosage forms,and dosing regimens which comprise SNS-595, and a second, or additional,active agent. Second active agents include specific combinations, or“cocktails,” of drugs or therapy, or both.

4. BRIEF DESCRIPTION OF FIGURES

FIG. 1 depicts the plasma concentrations of SNS-595 over time among thevarious patient cohorts dosed in the qwk×3 schedule.

FIG. 2 illustrates nuclear foci formation in HCT116 cells aftertreatment with SNS-595, etoposide, bleomycin and cisplatin;

FIG. 3 depicts foci quantitation by measuring foci fluorescentintensity;

FIG. 4 illustrates dependence of foci formation on dose and time;

FIG. 5 shows cells with more than 2 foci as a function of time andSNS-595 concentration;

FIG. 6, illustrates DNA damage induced by SNS-595 and etoposide in thepresence and absence of caffeine, which is an inhibitor of ATM and ATR.

FIG. 7 shows DNA damage induced by SNS-595 and etoposide in the presence(MO59K cells) and absence (MO59J cells) of DNA-PK;

FIGS. 8 a-c demonstrate synergistic/additive effect of co-dosing SNS-595with various cytotoxic agents in HCT 116 colon carcinoma cells; and

FIG. 8 d demonstrates synergistic/additive effect of co-dosing SNS-595with various cytotoxic agents in H460 lung cancer cells;

FIG. 9 shows combination index when SNS-595 is dosed simultaneously witha selection of DNA damaging agents and antimetabolites in SKOV3 ovariancancer cell line (+/+) and (−/−) for p53 expression, shown as black andgrey diamonds, respectively; and

FIGS. 10 a-d demonstrate effect of co-dosing SNS-595 with variouscytotoxic agents in HCT 116 colon carcinoma cells.

FIG. 11 provides dose linearity of three weekly doses (qwk×3;circles=week 1; triangles=week 2) and once every three week doses (q3wk;diamonds) of SNS-595 in patients with advanced solid tumors.

FIG. 12 provides a comparison of anti-tumor activities of SNS-595,etoposide, doxorubicin and irinotecan in CCRF-CEM xenograft model.

FIG. 13 provides a comparison of anti-tumor activities of SNS-595 (at 20mg/kg and 25 mg/kg), etoposide, doxorubicin and irinotecan in LM3-Jckxenograft model.

FIG. 14 shows cellularity in bone marrow 6 days post initial injectionof SNS-595 in female CD-1 mice. SNS-595 was administered on day 0 andday 4. All images shown at 10× magnification;

FIG. 15 provides neutrophil response to SNS-595 dose;

FIG. 16 provides neutrophil count at various SNS-595 doses by day 8;

FIG. 17 provides WBC count at various SNS-595 doses by day 8;

FIG. 18 provides platelet count at various SNS-595 doses by day 8;

FIG. 19 provides percent change in body weight at various time intervalsafter administering SNS-595; and

FIG. 20 shows bone marrow rebound at day 12 after administering 20 mg/kgSNS-595.

5. DEFINITIONS

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art. All cited patents, applications, published applications andother publications are incorporated by reference in their entirety. Inthe event that there are a plurality of definitions for a term herein,those in this section prevail unless stated otherwise.

As used herein, enantiomerically pure(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid is substantially free from(−)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid (i.e., in enantiomeric excess). In other words, the “(+)” form of1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid is substantially free from the “(−)” form of the compound and is,thus, in enantiomeric excess of the “(−)” form. The term“enantiomerically pure” or “pure enantiomer” denotes that the compoundcomprises more than 75% by weight, more than 80% by weight, more than85% by weight, more than 90% by weight, more than 91% by weight, morethan 92% by weight, more than 93% by weight, more than 94% by weight,more than 95% by weight, more than 96% by weight, more than 97% byweight of the enantiomer.

As used herein and unless otherwise indicated, the term“enantiomerically pure(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid” refers to at least about 80% by weight(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid and at most about 20% by weight(−)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid, at least about 90% by weight(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid and at most about 10% by weight the (−)-enantiomer, at least about95% by weight(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid and at most about 5% by weight the (−)-enantiomer, at least about97% by weight(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid and at most about 3% by weight (−)-enantiomer.

As used herein and unless otherwise indicated, the terms “treat,”“treating” and “treatment” refer to alleviating or reducing the severityof a symptom associated with the disease or condition being treated.

The term “prevention” includes the inhibition of a symptom of theparticular disease or disorder. In some embodiments, patients withfamilial history of cancer are candidates for preventive regimens.Generally, the term “preventing” refers to administration of the drugprior to the onset of symptoms, particularly to patients at risk ofcancer.

As used herein and unless otherwise indicated, the term “managing”encompasses preventing the recurrence of the particular disease ordisorder in a patient who had suffered from it, lengthening the time apatient who had suffered from the disease or disorder remains inremission, reducing mortality rates of the patients, and/or maintaininga reduction in severity or avoidance of a symptom associated with thedisease or condition being managed.

As used herein “subject” is an animal, typically a mammal, includinghuman, such as a patient.

As used herein, the term “cancer” includes, but is not limited to, solidtumors and blood born tumors. The term “cancer” refers to disease ofskin tissues, organs, blood, and vessels, including, but not limited to,cancers of the bladder, bone or blood, brain, breast, cervix, chest,colon, endrometrium, esophagus, eye, head, kidney, liver, lung, mouth,neck, ovaries, pancreas, prostate, rectum, stomach, testis, throat, anduterus.

As used herein, “hematologic malignancy” refers to cancer of the body'sblood-forming and immune system—the bone marrow and lymphatic tissue.Such cancers include leukemias, lymphomas (Non-Hodgkin's Lymphoma),Hodgkin's disease (also called Hodgkin's Lymphoma) and myeloma.

The term “leukemia” refers to malignant neoplasms of the blood-formingtissues. The leukemia includes, but is not limited to, chroniclymphocytic leukemia, chronic myelocytic leukemia, acute lymphoblasticleukemia, acute myelogenous leukemia and acute myeloblastic leukemia.The leukemia can be relapsed, refractory or resistant to conventionaltherapy.

As used herein “promyelocytic leukemia” or “acute promyelocyticleukemia” refers to a malignancy of the bone marrow in which there is adeficiency of mature blood cells in the myeloid line of cells and anexcess of immature cells called promyelocytes. It is usually marked byan exchange of parts of chromosomes 15 and 17.

As used herein “acute lymphocytic leukemia (ALL)”, also known as “acutelymphoblastic leukemia” refers to a malignant disease caused by theabnormal growth and development of early nongranular white blood cell orlymphocytes.

As used herein “T-cell leukemia” refers to a disease in which certaincells of the lymphoid system called T lymphocytes or T cells aremalignant. T cells are white blood cells that normally can attackvirus-infected cells, foreign cells and cancer cells and producesubstances that regulate the immune response.

The term “relapsed” refers to a situation where patients who have had aremission of cancer after therapy have a return of cancer cells.

The term “refractory or resistant” refers to a circumstance wherepatients, even after intensive treatment, have residual cancer cells intheir body.

As used herein, the IC₅₀ refers to an amount, concentration or dosage ofa particular test compound that achieves a 50% inhibition of a maximalresponse in an assay that measures such response.

As used herein, and unless otherwise specified, the terms“therapeutically effective amount” and “effective amount” of a compoundrefer to an amount sufficient to provide a therapeutic benefit in thetreatment, prevention and/or management of a disease, to delay orminimize one or more symptoms associated with the disease or disorder tobe treated. The terms “therapeutically effective amount” and “effectiveamount” can encompass an amount that improves overall therapy, reducesor avoids symptoms or causes of disease or disorder or enhances thetherapeutic efficacy of another therapeutic agent.

As used herein and unless otherwise indicated, the term“pharmaceutically acceptable salt” includes, but is not limited to,salts of acidic or basic groups that can be present in the compoundsprovided herein. Under certain acidic conditions, the compound can forma wide variety of salts with various inorganic and organic acids. Theacids that can be used to prepare pharmaceutically acceptable salts ofsuch basic compounds are those that form salts comprisingpharmacologically acceptable anions including, but not limited to,acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide,calcium edetate, camsylate, carbonate, chloride, bromide, iodide,citrate, dihydrochloride, edetate, edisylate, estolate, esylate,fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate,hexylresorcinate, hydrabamine, hydroxynaphthoate, isethionate, lactate,lactobionate, malate, maleate, mandelate, mesylate, methylsulfate,muscate, napsylate, nitrate, panthothenate, phosphate/diphosphate,polygalacturonate, salicylate, stearate, succinate, sulfate, tannate,tartrate, teoclate, triethiodide and pamoate. Under certain basicconditions, the compound can form base salts with variouspharmacologically acceptable cations. Non-limiting examples of suchsalts include alkali metal or alkaline earth metal salts and,particularly, calcium, magnesium, sodium, lithium, zinc, potassium andiron salts.

As used herein and unless otherwise indicated, the term “hydrate” meansa compound provided herein or a salt thereof, that further includes astoichiometric or non-stoichiometeric amount of water bound bynon-covalent intermolecular forces.

As used herein and unless otherwise indicated, the term “solvate” meansa solvate formed from the association of one or more solvent moleculesto a compound provided herein. The term “solvate” includes hydrates(e.g., mono-hydrate, dihydrate, trihydrate, tetrahydrate and the like).

The terms “co-administration” and “in combination with” include theadministration of two therapeutic agents (for example, SNS-595 andanother anti-cancer agent or second agent) either simultaneously,concurrently or sequentially with no specific time limits. In oneembodiment, both agents are present in the cell or in the patient's bodyat the same time or exert their biological or therapeutic effect at thesame time. In one embodiment, the two therapeutic agents are in the samecomposition or unit dosage form. In another embodiment, the twotherapeutic agents are in separate compositions or unit dosage forms.

The term “the supportive care agent” refers to any substance thattreats, prevents or manages an adverse effect from SNS-595 treatment.

6. DETAILED DESCRIPTION 6.1 SNS-595

The compound for use in the methods and compositions provided herein isenantiomerically pure(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid, which is also known as SNS-595 or AG-7352. SNS-595 has thefollowing chemical structure:

In certain embodiments, pharmaceutically acceptable salts, solvates,hydrates or prodrugs of SNS-595 are used in the methods and compositionsprovided herein.

SNS-595 can be prepared by methods known to one of skill in the art, forexample, according to the preparation procedure for Example C-1 of U.S.Pat. No. 5,817,669, titled “Compounds, processes for the preparationthereof and anti-tumor agents,” issued Oct. 6, 1998, and in JapanesePatent Application No. Hei 10-173986, to Chikugi et al., both of whichare incorporated herein by reference in their entirety. Certainexemplary pharmaceutical compositions comprising SNS-595 and methods ofusing the same are described in U.S. Patent Application Pub. Nos.2005-0203120; 2005-0215583 and 2006-0025437, all of which areincorporated herein by reference in their entirety.

6.2 Methods of Use

Proliferating cells undergo four phases of the cell cycle: G₁, S, G₂,and M. These phases were first identified by observing dividing cells asthe cells progressed through DNA synthesis which became known as thesynthesis or S phase of the cell cycle and mitosis and is known as themitotic or M phase or S phase of the cell cycle. The observed gaps intime between the completion of DNA synthesis and mitosis and betweenmitosis to the next cycle of DNA synthesis are as the G₁ and G₂ phasesrespectfully. Non-proliferating cells that retain the ability toproliferate under the appropriate conditions are quiescent or in the G₀state and are typically characterized as having exited the cell cycle.

SNS-595 is a cell cycle inhibitor and arrests cells at the G₂ interface.Without being limited by a particular theory, SNS-595 mediates theactivation of the DNA-PK pathway which eventually leads to apoptoticcell death. These events are S-phase specific, i.e., they occur onlyduring the S phase of the cell cycle. Without being limited by aparticular theory, treatment with SNS-595 results in an increase in thenumber of double-strand DNA breaks that form during the S phase. Thisdamage impedes the ability of the cell to synthesize DNA and lengthensthe time the cell spends in the S phase. Once DNA damage is detected incells, markers for apoptosis rapidly appear. This rapid onset ofapoptosis appears to be p73 dependent as shown by a more than 11 folddecrease in SNS-595 sensitivity in p73 null cells as compared to p73containing cells.

As FIG. 7 exemplifies, the formation of double-strand breaks activates,in a dose dependent manner, the DNA-PK mediated repair and apoptoticcellular machinery including but not limited to: i) DNA-PK expression;ii) H2AX phosphorylation; iii) c-Abl phosphorylation; iv) p53phosphorylation; v) p73 phosphorylation; vi) p21 expression; vii)caspase-9 activation; and viii) caspase-3 activation. When the DNAdamage is sufficiently severe such that the double-strand breaks cannotbe repaired through non-homologous end joining (NHEJ), the cell rapidlyenters apoptosis. Some cells are able to reach the G₂ phase but aresubsequently arrested (mediated by cdc2/cyclin B) because the cells aretoo damaged to enter into the M phase and also eventually becomesapoptotic. Without being limited by a particular theory, because SNS-595is S-phase selective, doses of SNS-595 that are cytotoxic toproliferating cells (thus are progressing through the cell cycleincluding the S phase) are non-lethal to non-proliferating cells.

6.2.1 Solid Tumors

Accordingly, provided herein are methods of treating, managing, orpreventing cancers comprising administering a dose of about 1 mg/m² toabout 100 mg/m² of SNS-595 to a mammal in need of such treatment,management or prevention. The cancer types include, but are not limitedto, bladder cancer, breast cancer, cervical cancer, colon cancer(including colorectal cancer), esophageal cancer, head and neck cancer,liver cancer, lung cancer (both small cell and non-small cell),melanoma, myeloma, neuroblastoma, ovarian cancer, pancreatic cancer,prostate cancer, renal cancer, sarcoma (including osteosarcoma), skincancer (including squamous cell carcinoma), stomach cancer, testicularcancer, thyroid cancer, and uterine cancer. In one embodiment, themethods encompass treating, preventing or managing colon, pancreas,breast, mesothelioma, cholangiocarcinoma, leiomyosarcoma, liposarcoma,melanoma, nasopharyngeal, neuroendocrine, ovarian, renal, salivarygland, small cell lung cancer, or spindle cell carcinoma.

6.2.2 Leukemias

In one embodiment, methods provided herein encompass treating,preventing or managing various types of leukemias such as chroniclymphocytic leukemia, chronic myelocytic leukemia, acute lymphoblasticleukemia, acute myelogenous leukemia, and acute myeloblastic leukemia.

In some embodiments, the methods encompass treating, preventing ormanaging acute leukemia, such as AML, which includes, but is not limitedto undifferentiated AML (M0), myeloblastic leukemia (M1), myeloblasticleukemia (M2), promyelocytic leukemia (M3 or M3 variant [M3V]),myelomonocytic leukemia (M4 or M4 variant with eosinophilia [M4E]),monocytic leukemia (M5), erythroleukemia (M6), megakaryoblastic leukemia(M7). In some embodiments, acute lymphocytic leukemia (ALL) includesleukemia that originates in the blast cells of the bone marrow(B-cells), thymus (T-cells), and lymph nodes. The acute lymphocyticleukemia is categorized according to the French-American-British (FAB)Morphological Classification Scheme as L1-Mature-appearing lymphoblasts(T-cells or pre-B-cells), L2—Immature and pleomorphic (variously shaped)lymphoblasts (T-cells or pre-B-cells), and L3—Lymphoblasts (B-cells;Burkitt's cells).

In one embodiment, the acute myelogenous leukemia is undifferentiatedAML (M0).

In one embodiment, the acute myelogenous leukemia is myeloblasticleukemia (M1).

In one embodiment, the acute myelogenous leukemia is myeloblasticleukemia (M2).

In one embodiment, the acute myelogenous leukemia is promyelocyticleukemia (M3 or M3 variant [M3V]).

In one embodiment, the acute myelogenous leukemia is myelomonocyticleukemia (M4 or M4 variant with eosinophilia [M4E]).

In one embodiment, the acute myelogenous leukemia is monocytic leukemia(M5).

In one embodiment, the acute myelogenous leukemia is erythroleukemia(M6).

In one embodiment, the acute myelogenous leukemia is megakaryoblasticleukemia (M7).

In one embodiment, the acute lymphocytic leukemia originates in theblast cells of the bone marrow (B-cells)

In one embodiment, the acute lymphocytic leukemia originates in thethymus (T-cells).

In one embodiment, the acute lymphocytic leukemia originates in thelymph nodes.

In one embodiment, the acute lymphocytic leukemia is L1 typecharacterized by mature-appearing lymphoblasts (T-cells or pre-B-cells).

In one embodiment, the acute lymphocytic leukemia is L2 typecharacterized by immature and pleomorphic (variously shaped)lymphoblasts (T-cells or pre-B-cells).

In one embodiment, the acute lymphocytic leukemia is L3 typecharacterized by lymphoblasts (B-cells; Burkitt's cells).

In certain embodiments, the acute myelogenous leukemia is promyelocyticleukemia, or lymphoblastic leukemia. In certain embodiments, the acutelymphocytic leukemia is T-cell leukemia. In one embodiment, methodsprovided herein encompass methods of treating, preventing or managingpromyelocytic leukemia, T-cell leukemia or lymphoblastic leukemia. Inone embodiment, the T-cell leukemia is peripheral T-cell leukemia,T-cell lymphoblastic leukemia, cutaneous T-cell leukemia, and adultT-cell leukemia.

In some embodiments, SNS-595 is used to treat drug resistant leukemias,such as chronic myelogenous leukemia (CML). Thus, treatment with SNS-595could provide an alternative for patients who do not respond to othermethods of treatment. In some embodiments, such other methods oftreatment encompass treatment with Gleevac®. In some embodiments,provided herein are methods of treatment of Philadelphia chromosomepositive chronic myelogenous leukemia (Ph+CML). In some embodiments,provided herein are methods of treatment of Gleevac® resistantPhiladelphia chromosome positive chronic myelogenous leukemia (Ph+CML).

The methods provided herein encompass treating patients who have beenpreviously treated for cancer, but are non-responsive to standardtherapies, as well as those who have not previously been treated. Alsoencompassed are methods of treating patients regardless of patient'sage, although some diseases or disorders are more common in certain agegroups. Further provided are methods of treating patients who haveundergone surgery in an attempt to treat the disease or condition atissue, as well as those who have not. Because patients with cancer haveheterogenous clinical manifestations and varying clinical outcomes, thetreatment given to a patient may vary, depending on his/her prognosis.The skilled clinician will be able to readily determine without undueexperimentation specific secondary agents, types of surgery, and typesof non-drug based standard therapy that can be effectively used to treatan individual patient with cancer.

The administered dose of SNS-595 can be delivered as a single dose suchas, for example, an IV push of 10-15 minutes duration (e.g. a singlebolus injection) or over time such as, for example, a 24-hour period(e.g., continuous infusion over time or divided bolus doses over time)and is repeated as necessary, for example, until the patient experiencesstable disease or regression, or until the patient experiences diseaseprogression or unacceptable toxicity. For example, stable disease forsolid tumors generally means that the perpendicular diameter ofmeasurable lesions has not increased by 25% or more from the lastmeasurement. See e.g., Response Evaluation Criteria in Solid Tumors(RECIST) Guidelines, Journal of the National Cancer Institute 92(3):205-216 (2000). Stable disease or lack thereof is determined by methodsknown in the art such as evaluation of patient symptoms, physicalexamination, visualization of the tumor that has been imaged usingX-ray, CAT, PET, or MRI scan and other commonly accepted evaluationmodalities.

In another embodiment, the dose is about 10 mg/m²-100 mg/m². In anotherembodiment, the dose is about 30 mg/m²-75 mg/m². In another embodiment,the dose is about 40 mg/m²-80 mg/m². In another embodiment, the dose isabout 50 mg/m²-90 mg/m². In another embodiment, the dose is about 15mg/m²-80 mg/m².

In another embodiment the dose is about 20 mg/m²-30 mg/m². In anotherembodiment the dose is about 25 mg/m²-35 mg/m². In another embodimentthe dose is about 40 mg/m²-50 mg/m². In another embodiment the dose isabout 45 mg/m²-55 mg/m². In another embodiment the dose is about 50mg/m²-60 mg/m². In another embodiment the dose is about 55 mg/m²-65mg/m². In another embodiment the dose is about 60 mg/m²-70 mg/m². Inanother embodiment the dose is about 65 mg/m²-75 mg/m². In anotherembodiment the dose is about 70 mg/m²-80 mg/m². In another embodimentthe dose is about 75 mg/m²-85 mg/m². In another embodiment the dose isabout 80 mg/m²-90 mg/m². In another embodiment the dose is about 85mg/m²-95 mg/m². In another embodiment the dose is about 90 mg/m²-100mg/m².

In other embodiments, SNS-595 is administered in combination withanother drug (“second active agent”) or another therapy for treating,managing, or preventing cancer. Second active agents include smallmolecules and large molecules (e.g., proteins and antibodies), examplesof which are provided herein, as well as stem cells or cord blood.Methods, or therapies, that can be used in combination with theadministration of an SNS-595 include, but are not limited to, surgery,immunotherapy, biological therapy, radiation therapy and other non-drugbased therapies presently used to treat, prevent or manage cancer.Various dosing regimens for administration of SNS-595 alone and/or incombination therapy are discussed herein.

Also provided are pharmaceutical compositions (e.g., single unit dosageforms) that can be used in methods disclosed herein. Particularpharmaceutical compositions comprise SNS-595 and a second active agent.

6.3 Doses and Dosing Regimens

In one embodiment, the methods of treating, preventing or managingcancers provided herein comprise administering to a patient on the basisof body surface area, a dose of about 1 mg/m² to 150 mg/m² of SNS-595.In another embodiment, the methods of comprise administering a dose ofabout 1 mg/m² to 100 mg/m² of SNS-595. In another embodiment, themethods of comprise administering a dose of about 1 mg/m² to 75 mg/m² ofSNS-595. In another embodiment, the methods of comprise administering adose of about 1 mg/m² to 60 mg/m² of SNS-595. In another embodiment, themethods of comprise administering a dose of about 1 mg/m² to 50 mg/m² ofSNS-595. In another embodiment, the methods of comprise administering adose of about 1 mg/m² to 48 mg/m² of SNS-595. In another embodiment, themethods of comprise administering a dose of about 1 mg/m² to 24 mg/m² ofSNS-595. In another embodiment, the methods of comprise administering adose of about 3 mg/m² to 27 mg/m² of SNS-595 on the basis of bodysurface area. In another embodiment, the methods of compriseadministering a dose of about 3 mg/m² to 24 mg/m² of SNS-595 on thebasis of body surface area. In another embodiment, the methods ofcomprise administering a dose of about 10 mg/m² to 90 mg/m² of SNS-595on the basis of body surface area. In another embodiment, the methods ofcomprise administering a dose of about 15 mg/m² to 80 mg/m² of SNS-595on the basis of body surface area. Body surface area calculations can becalculated for example, with the Mosteller formula wherein:

BSA(m²)=square root of [(height(cm)×weight(kg)/3600].

In another embodiment, the dose is 3 mg/m² to 24 mg/m² on the basis ofbody surface area. In another embodiment, the dose is 3 mg/m² to 18mg/m² on the basis of body surface area. In another embodiment, the doseis 3 mg/m² to 15 mg/m². In another embodiment, the dose is 1 mg/m², 2mg/m², 3 mg/m², 4 mg/m², 5 mg/m², 6 mg/m², 7 mg/m², 8 mg/m², 9 mg/m², 10mg/m², 11 mg/m², 12 mg/m², 13 mg/m², 14 mg/m², 15 mg/m², 16 mg/m², 17mg/m², 18 mg/m², 19 mg/m², 20 mg/m², 21 mg/m², 22 mg/m², 23 mg/m², 24mg/m², 25 mg/m², 26 mg/m², 27 mg/m², 30 mg/m², 36 mg/m², 42 mg/m², 48mg/m², 50 mg/m², 55 mg/m², 60 mg/m² or 65 mg/m² on the basis of bodysurface area. In another embodiment, the dose is 3 mg/m², 6 mg/m², 9mg/m², 12 mg/m², 15 mg/m², 18 mg/m², 21 mg/m² 24 mg/m², 25 mg/m², 27mg/m², 36 mg/m², 48 mg/m² or 50 mg/m².

In one embodiment, the dose is 15 mg/m² on the basis of body surfacearea. In another embodiment, the dose is 25 mg/m² on the basis of bodysurface area. In another embodiment, the dose is 30 mg/m² on the basisof body surface area. In one embodiment, the dose is 50 mg/m² on thebasis of body surface area.

In another embodiment, the dose is 15 mg/m² to 80 mg/m² on the basis ofbody surface area. In another embodiment, the dose is 15 mg/m² to 75mg/m² on the basis of body surface area. In another embodiment, the doseis 20 mg/m² to 65 mg/m². In another embodiment, the dose is 30 mg/m² to50 mg/m². In another embodiment, the dose is 15 mg/m², 20 mg/m², 25mg/m², 30 mg/m², 35 mg/m², 40 mg/m², 45 mg/m², 50 mg/m², 55 mg/m², 60mg/m², 65 mg/m², 70 mg/m², 75 mg/m², or 80 mg/m² on the basis of bodysurface area.

The administered dose of SNS-595 can be expressed in units other than asmg/m². For example, doses can be expressed as mg/kg. One of ordinaryskill in the art would readily know how to convert doses from mg/m² tomg/kg to given either the height or weight of a subject or both (see,http:///wwwfda.gov/cder/cancer/animalframe.htm). For example, a dose of1 mg/m² to 30 mg/m² for a 65 kg human is approximately equal to 0.026mg/kg to 0.79 mg/kg. In another example, a dose of 3 mg/m² for a 65 kghuman is approximately equal to 0.078 mg/kg. In another example, a doseof 15 mg/m² to 80 mg/m² for a 65 kg human is approximately equal to 0.39mg/kg to 2.11 mg/kg.

In certain embodiments, the administered dose of SNS-595 can bedelivered as a single dose such as, for example, an IV push of 10-15minutes duration (e.g. a single bolus IV injection) or over time suchas, for example, a 24-hour period (e.g., continuous infusion over timeor divided bolus doses over time) and is repeated as necessary, forexample, until the patient experiences stable disease or regression oruntil the patient experiences disease progression or unacceptabletoxicity. Stable disease or lack thereof is determined by methods knownin the art, such as evaluation of patient symptoms, physical examinationand other commonly accepted evaluation modalities.

The amount of the pharmaceutical composition administered according tothe methods provided herein will depend on the mammal being treated, theseverity of the disorder or symptom of the disorder, the manner ofadministration, the frequency of administration and the judgment of theprescribing physician.

In some embodiments, the frequency of administration is in the range ofabout a daily dose to about a monthly dose. In certain embodiments,administration is once a day, once every other day, twice a week, onceevery week, once every two weeks, once every three weeks, or once everyfour weeks. In one embodiment, the pharmaceutical composition providedherein is administered weekly.

In certain embodiments, SNS-595 is cyclically administered to a patient.Cycling therapy involves the administration of an active agent for aperiod of time, followed by a rest for a period of time, and repeatingthis sequential administration. Cycling therapy can reduce thedevelopment of resistance to one or more of the therapies, avoid orreduce the side effects of one of the therapies, and/or improves theefficacy of the treatment.

Consequently, in one embodiment, SNS-595 is administered weekly in asingle or divided doses in a three to six week cycle with a rest periodof about 1 to about 30 days. In another embodiment, SNS-595 isadministered weekly in a single or divided doses for one week, twoweeks, three weeks, four weeks, five weeks or six weeks with a restperiod of 1, 3, 5, 7, 9, 12, 14, 16, 18, 20, 22, 24, 26, 28, 29 or 30days. In some embodiments, the waiting period is 14 days. In someembodiments, the waiting period is 28 days. In one embodiment, thewaiting period is until there is sufficient bone marrow recovery. Thefrequency, number and length of dosing cycles can be increased ordecreased. Thus, another embodiment encompasses the administration ofSNS-595 for more cycles than are typical when it is administered alone.

In one embodiment, the methods provided herein comprise: i)administering a dose of about 1 mg/m² to 150 mg/m² of SNS-595 to apatient; ii) waiting a period of at least one day where the mammal isnot administered any SNS-595; and iii) administering another dose ofabout 1 mg/m² to 150 mg/m² of SNS-595 to the patient. In one embodiment,steps ii)-iii) are repeated a plurality of times. In another embodiment,the method comprises administering a dose of 1 mg/m²-100 mg/m² in stepsi) and iii).

In one embodiment, for example, in methods for treatment of certainleukemias, the methods provided herein comprise: i) administering a doseof about 10 mg/m²-150 mg/m² of SNS-595 to a mammal; ii) waiting a periodof at least one day where the mammal is not administered any SNS-595;iii) administering another dose of about 10 mg/m²-150 mg/m² of SNS-595to the mammal; and, iv) repeating steps ii)-iii) a plurality of times.In another embodiment, the method comprises administering a dose of 10mg/m²-100 mg/m² in steps i) and iii).

In one embodiment, the methods provided herein comprise: i)administering a dose of about 1 mg/m² to 75 mg/m² of SNS-595 to apatient; ii) waiting a period of at least one day where the mammal isnot administered any SNS-595; and iii) administering another dose ofabout 1 mg/m² to 75 mg/m² of SNS-595 to the patient. In one embodiment,steps ii)-iii) are repeated a plurality of times.

In one embodiment, the methods provided herein comprise: i)administering a dose of about 1 mg/m² to 48 mg/m² of SNS-595 to apatient; ii) waiting a period of at least one day where the mammal isnot administered any SNS-595; and iii) administering another dose ofabout 1 mg/m² to 48 mg/m² of SNS-595 to the patient. In one embodiment,steps ii)-iii) are repeated a plurality of times.

In one embodiment, the methods provided herein comprise: i)administering a dose of about 1 mg/m² to 24 mg/m² of SNS-595 to apatient; ii) waiting a period of at least one day where the mammal isnot administered any SNS-595; and iii) administering another dose ofabout 1 mg/m² to 24 mg/m² of SNS-595 to the patient. In one embodiment,steps ii)-iii) are repeated a plurality of times.

In another embodiment, the method comprises administering a dose ofabout 3 mg/m² to 24 mg/m² in steps i) and iii). In yet anotherembodiment, the method comprises administering a dose of about 15 mg/m²in steps i) and iii). In yet another embodiment, the method comprisesadministering a dose of about 1 mg/m² to 40 mg/m², about 1.5 mg/m² to 30mg/m², about 2 mg/m² to 25 mg/m² or about 3 mg/m² to 24 mg/m² in stepsi) and iii).

In another embodiment, the method comprises administering a dose ofabout 15 mg/m² to 80 mg/m² in steps i) and iii). In yet anotherembodiment, the method comprises administering a dose of about 15 mg/m²to 75 mg/m² in steps i) and iii). In yet another embodiment, the methodcomprises administering a dose of about 20 mg/m² to 65 mg/m², about 30mg/m² to 50 mg/m², about 35 mg/m², about 40 mg/m², or about 45 mg/m² insteps i) and iii).

In the above methods, for example, if the waiting period were 6 days,then the initial dose of SNS-595 is administered on Day 1 (step i); thewaiting period is six days (step ii); and the following dose of SNS-595is administered on Day 8 (step iii). Other exemplary time periodsinclude 2 days, 3 days, 5 days, 7 days, 10 days, 12 days, 13 days, 14days, 15 days, 17 days, 20 days, 27 days and 28 days. In anotherembodiment, the waiting period is at least 2 days and steps ii) throughiii) are repeated at least three times. In another embodiment, thewaiting period is at least 3 days and steps ii) through iii) arerepeated at least five times. In another embodiment, the waiting periodis at least 3 days and steps ii) through iii) are repeated at leastthree times. In another embodiment, the waiting period is at least 3days and steps ii) through iii) are repeated at least five times. Inanother embodiment, the waiting period is at least 6 days and steps ii)through iii) are repeated at least three times. In another embodiment,the waiting period is at least 6 days and steps ii) through iii) arerepeated at least five times. In another embodiment, the waiting periodis at least 14 days and steps ii) through iii) are repeated at leastthree times. In another embodiment, the waiting period is at least 20days and steps ii) through iii) are repeated at least three times. Inanother embodiment, the waiting period is at least 20 days and steps ii)through iii) are repeated at least five times. In another embodiment,the waiting period is at least 28 days and steps ii) through iii) arerepeated at least three times. In another embodiment, the waiting periodis at least 27 days and steps ii) through iii) are repeated at leastfive times. In another embodiment, the waiting period is at least 28days and steps ii) through iii) are repeated at least five times.

In another embodiment, the dosing method comprises administering a doseof SNS-595 twice a week (dosing on days 1, 4, 8 and 11) to a mammal. Inanother embodiment, the dosing method comprises administering a weeklydose of SNS-595 to a mammal. In another embodiment, the dosing methodcomprises administering a dose of SNS-595 to a mammal every two weeks.In another embodiment, the dosing method comprises administering a doseof SNS-595 to a mammal every three weeks. In another embodiment, thedosing method comprises administering a dose of SNS-595 to a mammalevery four weeks.

In another embodiment, the dosing method comprises a cycle wherein thecycle comprises administering a dose of SNS-595 to a mammal once a weekfor three weeks followed by a period of at least 14 days where noSNS-595 is administered to the mammal and wherein the cycle is repeateda plurality of times. In another embodiment, the period where no SNS-595is administered is 14 days. In another embodiment, the period where noSNS-595 is administered is 21 days.

In another embodiment, the methods provided herein comprise: i)administering a dose of about 1 mg/m² to 100 mg/m² of SNS-595 to amammal once a week for 3 weeks; ii) waiting a period of 14 days wherethe mammal is not administered any SNS-595; and iii) administeringanother dose of about 1 mg/m² to 100 mg/m² of SNS-595 to the mammal oncea week for 3 weeks. In one embodiment, steps ii)-iii) are repeated aplurality of times.

In another embodiment, the methods provided herein comprise: i)administering a dose of about 1 mg/m² to 75 mg/m² of SNS-595 to a mammalonce a week for 3 weeks; ii) waiting a period of 14 days where themammal is not administered any SNS-595; and iii) administering anotherdose of about 1 mg/m² to 75 mg/m² of SNS-595 to the mammal once a weekfor 3 weeks. In one embodiment, steps ii)-iii) are repeated a pluralityof times.

In another embodiment, the methods provided herein comprise: i)administering a dose of about 1 mg/m² to 60 mg/m² of SNS-595 to a mammalonce a week for 3 weeks; ii) waiting a period of 14 days where themammal is not administered any SNS-595; and iii) administering anotherdose of about 1 mg/m² to 60 mg/m² of SNS-595 to the mammal once a weekfor 3 weeks. In one embodiment, steps ii)-iii) are repeated a pluralityof times.

In another embodiment, the methods provided herein comprise: i)administering a dose of about 1 mg/m²-50 mg/m² of SNS-595 to a mammalonce a week for 3 weeks; ii) waiting a period of 14 days where themammal is not administered any SNS-595; iii) administering another doseof about 1 mg/m²-50 mg/m² of SNS-595 to the mammal once a week for 3weeks; and, iv) repeating steps ii)-iii) a plurality of times.

In another embodiment, the methods provided herein comprise: i)administering a dose of about 1 mg/m² to 48 mg/m² of SNS-595 to a mammalonce a week for 3 weeks; ii) waiting a period of 14 days where themammal is not administered any SNS-595; and iii) administering anotherdose of about 1 mg/m² to 48 mg/m² of SNS-595 to the mammal once a weekfor 3 weeks. In one embodiment, steps ii)-iii) are repeated a pluralityof times.

In another embodiment, the methods provided herein comprise: i)administering a dose of about 1 mg/m² to 24 mg/m² of SNS-595 to a mammalonce a week for 3 weeks; ii) waiting a period of 14 days where themammal is not administered any SNS-595; and iii) administering anotherdose of about 1 mg/m² to 24 mg/m² of SNS-595 to the mammal once a weekfor 3 weeks. In one embodiment, steps ii)-iii) are repeated a pluralityof times.

In another embodiment, the methods provided herein comprise: i)administering a dose of about 2 mg/m² to 40 mg/m² of SNS-595 to a mammalonce a week for 3 weeks; ii) waiting a period of 14 days where themammal is not administered any SNS-595; and iii) administering anotherdose of 2 mg/m² to 40 mg/m² of SNS-595 to the mammal once a week for 3weeks. In one embodiment, steps ii)-iii) are repeated a plurality oftimes.

In another embodiment, the methods provided herein comprise: i)administering a dose of about 3 mg/m² to 24 mg/m² of SNS-595 to a mammalonce a week for 3 weeks; ii) waiting a period of 14 days where themammal is not administered any SNS-595; and iii) administering anotherdose of about 3 mg/m² to 24 mg/m² of SNS-595 to the mammal once a weekfor 3 weeks. In one embodiment, steps ii)-iii) are repeated a pluralityof times.

In another embodiment, the methods provided herein comprise: i)administering a dose of about 3 mg/m² to 24 mg/m² of SNS-595 to a mammalonce a week for 3 weeks (e.g. dosing in days 1, 8 and 15); ii) waiting aperiod of at least 28 days where the mammal is not administered anySNS-595; and iii) administering another dose of about 3 mg/m² to 24mg/m² of SNS-595 to the mammal once a week for 3 weeks. In oneembodiment, steps ii)-iii) are repeated a plurality of times.

In another embodiment, the methods provided herein comprise: i)administering a dose of about 3 mg/m² to 24 mg/m² of SNS-595 to a mammaltwice a week for 2 weeks (dosing in days 1, 4, 8 and 11); ii) waiting aperiod of at least 28 days where the mammal is not administered anySNS-595; and iii) administering another dose of about 3 mg/m² to 24mg/m² of SNS-595 to the mammal twice a week for 2 weeks (dosing in days1, 4, 8 and 11). In one embodiment, steps ii)-iii) are repeated aplurality of times.

In another embodiment, the methods provided herein comprise: i)administering a dose of about 3 mg/m² to 24 mg/m² of SNS-595 to a mammalonce a week for 3 weeks (e.g. dosing in days 1, 8 and 15); ii) waiting aperiod of 28 days where the mammal is not administered any SNS-595; andiii) administering another dose of about 3 mg/m² to 24 mg/m² of SNS-595to the mammal once a week for 3 weeks. In one embodiment, steps ii)-iii)are repeated a plurality of times.

In another embodiment, the methods provided herein comprise: i)administering a dose of about 3 mg/m² to 24 mg/m² of SNS-595 to a mammaltwice a week for 2 weeks (dosing in days 1, 4, 8 and 11); ii) waiting aperiod of 28 days where the mammal is not administered any SNS-595; andiii) administering another dose of about 3 mg/m² to 24 mg/m² of SNS-595to the mammal twice a week for 2 weeks (dosing in days 1, 4, 8 and 11).In one embodiment, steps ii)-iii) are repeated a plurality of times.

In another embodiment, the methods provided herein comprise: i)administering a dose of about 15 mg/m² to 80 mg/m² of SNS-595 to amammal once a week for 3 weeks; ii) waiting a period of 14 days wherethe mammal is not administered any SNS-595; and iii) administeringanother dose of about 15 mg/m² to 80 mg/m² of SNS-595 to the mammal oncea week for 3 weeks. In one embodiment, steps ii)-iii) are repeated aplurality of times.

In another embodiment, the methods provided herein comprise: i)administering a dose of about 15 mg/m² to 80 mg/m² of SNS-595 to amammal once a week for 3 weeks (e.g. dosing in days 1, 8 and 15); ii)waiting a period of at least 28 days where the mammal is notadministered any SNS-595; and iii) administering another dose of about15 mg/m² to 80 mg/m² of SNS-595 to the mammal once a week for 3 weeks.In one embodiment, steps ii)-iii) are repeated a plurality of times.

In another embodiment, the methods provided herein comprise: i)administering a dose of about 15 mg/m² to 80 mg/m² of SNS-595 to amammal twice a week for 2 weeks (dosing in days 1, 4, 8 and 11); ii)waiting a period of at least 28 days where the mammal is notadministered any SNS-595; and iii) administering another dose of about15 mg/m² to 80 mg/m² of SNS-595 to the mammal twice a week for 2 weeks(dosing in days 1, 4, 8 and 11). In one embodiment, steps ii)-iii) arerepeated a plurality of times.

In another embodiment, the methods provided herein comprise: i)administering a dose of about 15 mg/m² to 80 mg/m² of SNS-595 to amammal once a week for 3 weeks (e.g. dosing in days 1, 8 and 15); ii)waiting a period of 28 days where the mammal is not administered anySNS-595; and iii) administering another dose of about 15 mg/m² to 80mg/m² of SNS-595 to the mammal once a week for 3 weeks. In oneembodiment, steps ii)-iii) are repeated a plurality of times.

In another embodiment, the methods provided herein comprise: i)administering a dose of about 15 mg/m² to 80 mg/m² of SNS-595 to amammal twice a week for 2 weeks (dosing in days 1, 4, 8 and 11); ii)waiting a period of 28 days where the mammal is not administered anySNS-595; and iii) administering another dose of about 15 mg/m² to 80mg/m² of SNS-595 to the mammal twice a week for 2 weeks (dosing in days1, 4, 8 and 11). In one embodiment, steps ii)-iii) are repeated aplurality of times.

In another embodiment, the method comprises administering a dose of 1mg/m² to 100 mg/m² of SNS-595 to a patient once a week wherein theone-week period comprises a treatment cycle and the treatment cycle isrepeated at least three times. In another embodiment, the methodcomprises administering a dose of 1 mg/m² to 75 mg/m² of SNS-595 to apatient once a week wherein the one-week period comprises a treatmentcycle and the treatment cycle is repeated at least three times. Inanother embodiment, the method comprises administering a dose of 1 mg/m²to 60 mg/m² of SNS-595 to a patient once a week wherein the one-weekperiod comprises a treatment cycle and the treatment cycle is repeatedat least three times. In another embodiment, the method comprisesadministering a dose of 1 mg/m² to 48 mg/m² of SNS-595 to a patient oncea week wherein the one-week period comprises a treatment cycle and thetreatment cycle is repeated at least three times. In another embodiment,the method comprises administering a dose of 1 mg/m² to 24 mg/m² ofSNS-595 to a patient once a week wherein the one-week period comprises atreatment cycle and the treatment cycle is repeated at least threetimes. In another embodiment, the dose is about 2 mg/m² to 40 mg/m² oncea week wherein the one-week period comprises a treatment cycle and thetreatment cycle is repeated at least three times. In another embodiment,the dose is about 3 mg/m² to 24 mg/m² once a week wherein the one-weekperiod comprises a treatment cycle and the treatment cycle is repeatedat least three times. In another embodiment, the dose is about 15 mg/m²once a week wherein the one-week period comprises a treatment cycle andthe treatment cycle is repeated at least three times.

In another embodiment, the method comprises administering a dose of 15mg/m² to 80 mg/m² of SNS-595 to a patient once a week wherein theone-week period comprises a treatment cycle and the treatment cycle isrepeated at least three times. In another embodiment, the methodcomprises administering a dose of 15 mg/m² to 75 mg/m² of SNS-595 to apatient once a week wherein the one-week period comprises a treatmentcycle and the treatment cycle is repeated at least three times. Inanother embodiment, the method comprises administering a dose of 20mg/m² to 65 mg/m² of SNS-595 to a patient once a week wherein theone-week period comprises a treatment cycle and the treatment cycle isrepeated at least three times. In another embodiment, the methodcomprises administering a dose of 30 mg/m² to 50 mg/m² of SNS-595 to apatient once a week wherein the one-week period comprises a treatmentcycle and the treatment cycle is repeated at least three times.

In some embodiments, the method comprises administering a dose of about1 mg/m² to 40 mg/m² of SNS-595 to a patient once a week (e.g. dosing indays 1, 8 and 15) wherein the one-week period comprises a treatmentcycle and the treatment cycle is repeated at least three times followedby a waiting period of at least 28 days. In some embodiments, the methodcomprises administering a dose of about 1 mg/m² to 40 mg/m² of SNS-595to a patient twice a week (dosing in days 1, 4, 8, and 11) wherein theone-week period comprises a treatment cycle and the treatment cycle isrepeated at least three times followed by a waiting period of at least28 days. In some embodiments, the method comprises administering a doseof about 1 mg/m² to 40 mg/m² of SNS-595 to a patient once a week (e.g.dosing in days 1, 8 and 15) wherein the one-week period comprises atreatment cycle and the treatment cycle is repeated at least three timesfollowed by a waiting period of 28 days. In some embodiments, the methodcomprises administering a dose of about 1 mg/m² to 40 mg/m² of SNS-595to a patient twice a week (dosing in days 1, 4, 8, and 11) wherein theone-week period comprises a treatment cycle and the treatment cycle isrepeated at least three times followed by a waiting period of 28 days.

In some embodiments, the method comprises administering a dose of about3 mg/m² to 24 mg/m² of SNS-595 to a patient once a week (e.g. dosing indays 1, 8 and 15) wherein the one-week period comprises a treatmentcycle and the treatment cycle is repeated at least three times followedby a waiting period of at least 28 days. In some embodiments, the methodcomprises administering a dose of about 3 mg/m² to 24 mg/m² of SNS-595to a patient twice a week (dosing in days 1, 4, 8, and 11) wherein theone-week period comprises a treatment cycle and the treatment cycle isrepeated at least three times followed by a waiting period of at least28 days. In some embodiments, the method comprises administering a doseof about 3 mg/m² to 24 mg/m² of SNS-595 to a patient once a week (e.g.dosing in days 1, 8 and 15) wherein the one-week period comprises atreatment cycle and the treatment cycle is repeated at least three timesfollowed by a waiting period of 28 days. In some embodiments, the methodcomprises administering a dose of about 3 mg/m² to 24 mg/m² of SNS-595to a patient twice a week (dosing in days 1, 4, 8, and 11) wherein theone-week period comprises a treatment cycle and the treatment cycle isrepeated at least three times followed by a waiting period of 28 days.

In some embodiments, the method comprises administering a dose of about15 mg/m² to 80 mg/m² of SNS-595 to a patient once a week (e.g. dosing indays 1, 8 and 15) wherein the one-week period comprises a treatmentcycle and the treatment cycle is repeated at least three times followedby a waiting period of at least 28 days. In some embodiments, the methodcomprises administering a dose of about 15 mg/m² to 80 mg/m² of SNS-595to a patient twice a week (dosing in days 1, 4, 8, and 11) wherein theone-week period comprises a treatment cycle and the treatment cycle isrepeated at least three times followed by a waiting period of at least28 days. In some embodiments, the method comprises administering a doseof about 15 mg/m² to 80 mg/m² of SNS-595 to a patient once a week (e.g.dosing in days 1, 8 and 15) wherein the one-week period comprises atreatment cycle and the treatment cycle is repeated at least three timesfollowed by a waiting period of 28 days. In some embodiments, the methodcomprises administering a dose of about 15 mg/m² to 80 mg/m² of SNS-595to a patient twice a week (dosing in days 1, 4, 8, and 11) wherein theone-week period comprises a treatment cycle and the treatment cycle isrepeated at least three times followed by a waiting period of 28 days.

In another embodiment, the method comprises administering a dose ofabout 1 mg/m²-50 mg/m² of SNS-595 to a mammal once a week wherein theone-week period comprises a treatment cycle and the treatment cycle isrepeated at least twice. In another embodiment, the dose is about 2mg/m²-40 mg/m². In another embodiment, the dose is about 3 mg/m²-24mg/m². In another embodiment, the dose is about 4 mg/m²-20 mg/m².

6.4 Exemplary Dosing Regimens

Exemplary dosing regimens in connection with specific cancers areprovide below. These dosing regimens are intended to be illustrative,but not exclusive.

In one aspect a method of treating a solid tumor is provided. The methodcomprises:

-   -   i) administering a dose of about 1 mg/m² to 100 mg/m² of SNS-595        to a patient;    -   ii) waiting a period of at least six days where the subject is        not administered any SNS-595;    -   iii) administering another dose of about 1 mg/m² to 100 mg/m² of        SNS-595 to the patient; and,    -   iv) repeating steps ii)-iii) a plurality of times.

In another aspect, a method of treating solid tumors comprisesadministering a dose of about 1 mg/m² to 75 mg/m² of SNS-595 to apatient once a week wherein the one-week period comprises a treatmentcycle and the treatment cycle is repeated at least twice. In anotherembodiment, the dose is about 15 mg/m² to 80 mg/m². In anotherembodiment, the dose is about 3 mg/m² to 24 mg/m².

In another aspect, the method of treating solid tumors comprisesadministering a dose of about 15 mg/m² to 40 mg/m² of SNS-595 to apatient once a week for three weeks followed by a period of at least twoweeks where no SNS-595 is administered to said subject and wherein thecycle is repeated a plurality of times. In another embodiment, the doseis about 15 mg/m² to 35 mg/m². In another embodiment, the dose is about20 mg/m² to 30 mg/m². In another embodiment, the dose is about 20 mg/m²to 25 mg/m².

In another aspect, the method of treating solid tumors comprisesadministering a dose of about 35 mg/m² to 80 mg/m² of SNS-595 to apatient once in a three-week period wherein the three week periodcomprises a treatment cycle and the treatment cycle is repeated at leasttwice.

In another aspect, a method of treating hematologic malignancies areprovided herein. Such methods, in certain embodiment, compriseadministering a dose of about 20 mg/m² to 60 mg/m² of SNS-595 to apatient.

In patients who are considered heavily pretreated (“heavily pretreatedpatients”), the method comprises administering a dose of 35 mg/m² to 60mg/m² of SNS-595 to a patient once in a three week period wherein thethree week period comprises a treatment cycle and the treatment cycle isrepeated at least twice. In another embodiment, the method for treatinga heavily pretreated patient comprises, administering a dose of 40 mg/m²to 50 mg/m². In another embodiment, the method for treating a heavilypretreated patient, comprises administering a dose of 45 mg/m² to 50mg/m². A heavily pretreated patient is defined as described by Tolcheret al., J. Clin. Oncol. 19: 2937-2947 (2001) and is a patient who hasbeen treated previously with more than six courses of an alkylatingagent-containing chemotherapy regimen, more than two courses ofcarboplatin or mitomycin C, any prior nitrosourea-containing regimen,irradiation to 25% of the bone-marrow containing areas, high-dosechemotherapy requiring hematopoietic stem-cell reinfusions, orwidespread metastases to bone.

Patients, who have not been treated previously for their solid tumors orhave been treated but are not considered heavily pretreated, areminimally pretreated (“minimally pretreated patients”). For treatingminimally pretreated patients, the method comprises administering a doseof 45 mg/m² to 80 mg/m² of SNS-595 to a patient once in a three weekperiod wherein the three week period comprises a treatment cycle and thetreatment cycle is repeated at least twice. In another embodiment, themethod for treating a minimally pretreated patient comprises,administering a dose of 50 mg/m² to 75 mg/m². In another embodiment, themethod for treating a minimally pretreated patient, comprisesadministering a dose of 55 mg/m² to 70 mg/m². In another embodiment, themethod for treating a minimally pretreated patient, comprisesadministering a dose of 55 mg/m² to 65 mg/m².

In another aspect, a method of treating a hematologic cancer such asleukemias and lymphomas is provided. The method comprises:

-   -   i) administering a dose of 10 mg/m²-50 mg/m² of SNS-595 to a        patient;    -   ii) waiting a period of at least two days where the subject is        not administered any SNS-595;    -   iii) administering another dose of 10 mg/m²-50 mg/m² of SNS-595        to the patient; and,    -   iv) repeating steps ii)-iii) a plurality of times.

In one embodiment, the waiting period is six days. In anotherembodiment, the waiting period is two days. In another embodiment, thewaiting period is three days.

In one embodiment, the method of treating hematologic malignancycomprises administering a dose of about 20 mg/m², 22 mg/m², 25 mg/m², 27mg/m² or 30 mg/m² of SNS-595 to a patient once a week wherein theone-week period comprises a treatment cycle and the treatment cycle isrepeated at least twice. In one embodiment, the method of treatinghematologic malignancy comprises administering a dose of about 25 mg/m²of SNS-595 to a patient once a week wherein the one-week periodcomprises a treatment cycle and the treatment cycle is repeated at leasttwice.

Other dosing schedules useful for treatment of patients with hematologicmalignacies can include about 25 mg/m² to about 50 mg/m² administeredtwice a week for two weeks. In another embodiment, the dosing schedulesuse in treatment of hematologic malignancies include about 30 mg/m² toabout 45 mg/m² administered twice a week for two weeks. In anotherembodiment, the dosing schedules for treatment of hematologicmalignancies include 30, 35, 40, or 45 mg/m² administered twice a weekfor two weeks.

In one embodiment, the method of treating hematologic malignancycomprises administering a dose of about 40 mg/m², 45 mg/m², 50 mg/m², 55mg/m² or 60 mg/m² of SNS-595 to a patient once in two weeks wherein thetwo-week period comprises a treatment cycle. In one embodiment, themethod of treating hematologic malignancy comprises administering a doseof about 50 mg/m² of SNS-595 to a patient once in two weeks wherein thetwo-week period comprises a treatment cycle.

6.5 Combination Therapy

In the methods and compositions provided herein, SNS-595 can be usedwith or combined with other pharmacologically active compounds (“secondactive agents”). It is believed that certain combinations worksynergistically in the treatment of particular types of cancers. SNS-595can also work to alleviate adverse effects associated with certainsecond active agents, and some second active agents can be used toalleviate adverse effects associated with SNS-595.

6.5.1 Second Active Agents

One or more second active ingredients or agents can be used in themethods and compositions provided herein together with SNS-595. Secondactive agents can be large molecules (e.g., proteins) or small molecules(e.g., synthetic inorganic, organometallic or organic molecules).

Examples of large molecule active agents include, but are not limitedto, hematopoietic growth factors, cytokines, and monoclonal andpolyclonal antibodies, particularly therapeutic antibodies to cancerantigens. Typical large molecule active agents are biological molecules,such as naturally occurring or artificially made proteins. Proteins thatare particularly useful in the methods and compositions provided hereininclude proteins that stimulate the survival and/or proliferation ofhematopoietic precursor cells and immunologically active poietic cellsin vitro or in vivo. Others stimulate the division and differentiationof committed erythroid progenitors in cells in vitro or in vivo.Particular proteins include, but are not limited to: interleukins, suchas IL-2 (including recombinant IL-II (“rIL2”) and canarypox IL-2),IL-10, IL-12, and IL-18; interferons, such as interferon alfa-2a,interferon alfa-2b, interferon alfa-n1, interferon alfa-n3, interferonbeta-I a, and interferon gamma-I b; GM-CF and GM-CSF; and EPO.

Particular proteins that can be used in the methods and compositionsinclude, but are not limited to: filgrastim, which is sold in the UnitedStates under the trade name Neupogen® (Amgen, Thousand Oaks, Calif.) andits derivatives including, but not limited to pegfilgrastim;sargramostim, which is sold in the United States under the trade nameLeukine® (Immunex, Seattle, Wash.); recombinant EPO, which is sold inthe United States under the trade name Epogen® (Amgen, Thousand Oaks,Calif.); epoetin alfa; and darbepoetin alfa.

Recombinant and mutated forms of GM-CSF can be prepared as described inU.S. Pat. Nos. 5,391,485; 5,393,870 and 5,229,496, all of which areincorporated herein by reference. Recombinant and mutated forms of G-CSFcan be prepared as described in U.S. Pat. Nos. 4,810,643; 4,999,291;5,528,823 and 5,580,755, all of which are incorporated herein byreference.

Also provided for use in combination with SNS-595 are native, naturallyoccurring, and recombinant proteins. Further encompassed are mutants andderivatives (e.g., modified forms) of naturally occurring proteins thatexhibit, in vivo, at least some of the pharmacological activity of theproteins upon which they are based. Examples of mutants include, but arenot limited to, proteins that have one or more amino acid residues thatdiffer from the corresponding residues in the naturally occurring formsof the proteins. Also encompassed by the term “mutants” are proteinsthat lack carbohydrate moieties normally present in their naturallyoccurring forms (e.g., nonglycosylated forms). Examples of derivativesinclude, but are not limited to, pegylated derivatives and fusionproteins, such as proteins formed by fusing IgG1 or IgG3 to the proteinor active portion of the protein of interest. See, e.g., Penichet, M. L.and Morrison, S. L., J. Immunol. Methods 248:91-101 (2001).

Antibodies that can be used in combination with SNS-595 includemonoclonal and polyclonal antibodies. Examples of antibodies include,but are not limited to, trastuzumab (Herceptin®), rituximab (Rituxan®),bevacizumab (Avastin™), pertuzumab (Omnitarg™), tositumomab (Bexxar®),edrecolomab (Panorex®), and G250. SNS-595 can also be combined with orused in combination with, anti-TNF-α antibodies, and/or anti-EGFRantibodies such as, for example, Erbitux® or panitumumab.

Large molecule active agents may be administered in the form ofanti-cancer vaccines. For example, vaccines that secrete or cause thesecretion of, cytokines such as IL-2, G-CSF, and GM-CSF can be used inthe methods and pharmaceutical compositions provided. See, e.g., Emens,L. A., et al., Curr. Opinion Mol. Ther. 3(1):77-84 (2001).

In contrast to the general rule that drugs with different mechanism ofactions be selected to maximize the likelihood for additivity or synergy(see e.g., Page, R. and Takimoto, C., “Principles of Chemotherapy”,Cancer Management: A Multidisciplinary Approach (2001), p. 23),combinations comprising SNS-595 and a second agent that also impedes DNAsynthesis were found to be additive or synergistic.

As used herein, an agent impedes DNA synthesis when it directly orindirectly affects a cell's ability to synthesize DNA or to repair DNAdamage. The agent can directly interact with DNA (e.g., bind to orintercalate with) or it can bind to a DNA-binding protein that isinvolved in DNA synthesis or DNA repair. In general, an agent thatimpedes DNA synthesis is active during the S phase but need not be Sphase specific.

Since SNS-595 affects the DNA-PK pathway, second agent may be an agentthat mediates its cytotoxicity through the DNA-PK pathway. One examplesis an agent that inhibits non-homologous endjoining repair such asDNA-PK inhibitors. As used herein, and unless otherwise indicated, theterm “DNA-PK inhibitor” means an agent that inhibits or interferes witha signaling pathway mediated by DNA-PK. The inhibition of the activityof DNA-PK may be direct (e.g., a catalytic inhibitor of DNA-PK itself)or indirect (e.g., an agent that interferes with the formation of theactive DNA-PK complex (DNA-PK, Ku70 and Ku80)). Other examples include,but are not limited to, ligase IV inhibitors and apoptosis enhancingagents such as, but not limited to, caspase-9 activators, caspase-3activators, and Hsp90 inhibitors.

Second active agents that are small molecules can also be used toalleviate adverse effects associated with the administration of SNS-595.However, like some large molecules, many are believed to be capable ofproviding a synergistic effect when administered with (e.g., before,after or simultaneously) SNS-595. Examples of small molecule secondactive agents include, but are not limited to, anti-cancer agents,antibiotics, immunosuppressive agents, and steroids.

Examples of anti-cancer agents include, but are not limited to,alkylating agents, anti-neoplastic agents, anti-metabolites (e.g.,folate analogs, purine analogs, adenosine analogs, pyrimidine analogs,and substituted ureas), platinum coordination complexes, topoisomeraseII inhibitors, and radiation.

Specific anticancer agents include, but are not limited to: acivicin;aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin;altretamine; ambomycin; ametantrone acetate; amsacrine; anastrozole;anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin;batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafidedimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine;busulfan; cactinomycin; calusterone; capecitabline; caracemide;carbetimer; carboplatin; carmustine; carubicin hydrochloride;carzelesin; cedefingol; celecoxib (COX-2 inhibitor); chlorambucil;cirolemycin; cisplatin; cladribine; crisnatol mesylate;cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicinhydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguaninemesylate; diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride;droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin;edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin;enpromate; epipropidine; epirubicin hydrochloride; erbulozole;erlotinib; esorubicin hydrochloride; estramustine; estramustinephosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine;fadrozole hydrochloride; fazarabine; fenretinide; floxuridine;fludarabine phosphate; fluorouracil; fluorocitabine; fosquidone;fostriecin sodium; gefitinib; gemcitabine; gemcitabine hydrochloride;hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine;iproplatin; irinotecan; irinotecan hydrochloride; lanreotide acetate;letrozole; leuprolide acetate; liarozole hydrochloride; lometrexolsodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine;mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate;melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium;metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin;mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride;mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran;paclitaxel; pegaspargase; peliomycin; pemetrexed; pentamustine;peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantronehydrochloride; plicamycin; plomestane; porfimer sodium; porfiromycin;prednimustine; procarbazine hydrochloride; puromycin; puromycinhydrochloride; pyrazofurin; riboprine; safingol; safingol hydrochloride;semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermaniumhydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin;sulofenur; talisomycin; tecogalan sodium; taxotere; tegafur;teloxantrone hydrochloride; temoporfin; teniposide; teroxirone;testolactone; thiamiprine; thioguanidine; thioguanine; thiotepa;tiazofurin; tirapazamine; toremifene citrate; trestolone acetate;triciribine phosphate; trimetrexate; trimetrexate glucuronate;triptorelin; tubulozole hydrochloride; uracil mustard; uredepa;vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate;vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate;vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate;vinzolidine sulfate; vorozole; zeniplatin; zinostatin; and zorubicinhydrochloride.

Other anti-cancer drugs include, but are not limited to: 20-epi-1,25dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin;acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists;altretamine; ambamustine; amidox; amifostine; aminolevulinic acid;amrubicin; amsacrine; anagrelide; anastrozole; andrographolide;angiogenesis inhibitors; antagonist D; antagonist G; antarelix;anti-dorsalizing morphogenetic protein-1; antiandrogen, prostaticcarcinoma; antiestrogen; antineoplaston; antisense oligonucleotides;aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators;apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine;atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3;azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol;batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine;beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid;bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine;bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane;buthionine sulfoximine; calcipotriol; calphostin C; camptothecinderivatives; capecitabine; carboxamide-amino-triazole;carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor;carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropinB; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost;cis-porphyrin; cladribine; clomifene analogues; clotrimazole;collismycin A; collismycin B; combretastatin A4; combretastatinanalogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8;cryptophycin A derivatives; curacin A; cyclopentanthraquinones;cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor;cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin;dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone;didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine;dihydrotaxol, 9-; dioxamycin; diphenyl spiromustine; docetaxel;docosanol; dolasetron; doxifluridine; doxorubicin; droloxifene;dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine;edrecolomab; eflornithine; elemene; emitefur; epirubicin; epristeride;estramustine analogue; estrogen agonists; estrogen antagonists;etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine;fenretinide; filgrastim; finasteride; flavopiridol; flezelastine;fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex;formestane; fostriecin; fotemustine; gadolinium texaphyrin; galliumnitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine;glutathione inhibitors; hepsulfam; heregulin; hexamethylenebisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene;idramantone; ilmofosine; ilomastat; imatinib (e.g., Gleevec®);imiquimod; immunostimulant peptides; insulin-like growth factor-1receptor inhibitor; interferon agonists; interferons; interleukins;iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine;isobengazole; isohomohalicondrin B; itasetron; jasplakinolide;kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin;lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemiainhibiting factor; leukocyte alpha interferon;leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole;linear polyamine analogue; lipophilic disaccharide peptide; lipophilicplatinum compounds; lissoclinamide 7; lobaplatin; lombricine;lometrexol; lonidamine; losoxantrone; loxoribine; lurtotecan; lutetiumtexaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A;marimastat; masoprocol; maspin; matrilysin inhibitors; matrixmetalloproteinase inhibitors; menogaril; merbarone; meterelin;methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine;mirimostim; mitoguazone; mitolactol; mitomycin analogues; mitonafide;mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene;molgramostim; Erbitux, human chorionic gonadotrophin; monophosphoryllipid A+myobacterium cell wall sk; mopidamol; mustard anticancer agent;mycaperoxide B; mycobacterial cell wall extract; myriaporone;N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip;naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin;nemorubicin; neridronic acid; nilutamide; nisamycin; nitric oxidemodulators; nitroxide antioxidant; nitrullyn; oblimersen (Genasense®);O⁶-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone;ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin;osaterone; oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analogues;paclitaxel derivatives; palauamine; palmitoylrhizoxin; pamidronic acid;panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase;peldesine; pentosan polysulfate sodium; pentostatin; pentrozole;perflubron; perfosfamide; perillyl alcohol; phenazinomycin;phenylacetate; phosphatase inhibitors; picibanil; pilocarpinehydrochloride; pirarubicin; piritrexim; placetin A; placetin B;plasminogen activator inhibitor; platinum complex; platinum compounds;platinum-triamine complex; porfimer sodium; porfiromycin; prednisone;propyl bis-acridone; prostaglandin J2; proteasome inhibitors; proteinA-based immune modulator; protein kinase C inhibitor; protein kinase Cinhibitors, microalgal; protein tyrosine phosphatase inhibitors; purinenucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine;pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists;raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors;ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re186 etidronate; rhizoxin; ribozymes; RII retinamide; rohitukine;romurtide; roquinimex; rubiginone B1; ruboxyl; safingol; saintopin;SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine;senescence derived inhibitor 1; sense oligonucleotides; signaltransduction inhibitors; sizofiran; sobuzoxane; sodium borocaptate;sodium phenylacetate; solverol; somatomedin binding protein; sonermin;sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin1; squalamine; stipiamide; stromelysin inhibitors; sulfinosine;superactive vasoactive intestinal peptide antagonist; suradista;suramin; swainsonine; tallimustine; tamoxifen methiodide; tauromustine;tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomeraseinhibitors; temoporfin; teniposide; tetrachlorodecaoxide; tetrazomine;thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic;thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroidstimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocenebichloride; topsentin; toremifene; translation inhibitors; tretinoin;triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron;turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors;ubenimex; urogenital sinus-derived growth inhibitory factor; urokinasereceptor antagonists; vapreotide; variolin B; velaresol; veramine;verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole;zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer.

Specific second active agents include, but are not limited to,rituximab, oblimersen (Genasense®), remicade, docetaxel, celecoxib,melphalan, dexamethasone (Decadron®), steroids, gemcitabine,cisplatinum, temozolomide, etoposide, cyclophosphamide, temodar,carboplatin, procarbazine, gliadel, tamoxifen, topotecan, methotrexate,Arisa®, taxol, taxotere, fluorouracil, leucovorin, irinotecan, xeloda,CPT-11, interferon alpha, pegylated interferon alpha (e.g., PEGINTRON-A), capecitabine, cisplatin, thiotepa, fludarabine, carboplatin,liposomal daunorubicin, cytarabine, doxetaxol, pacilitaxel, vinblastine,IL-2, GM-CSF, dacarbazine, vinorelbine, zoledronic acid, palmitronate,biaxin, busulphan, prednisone, bisphosphonate, arsenic trioxide,vincristine, doxorubicin (Doxil®), paclitaxel, ganciclovir, adriamycin,estramustine sodium phosphate (Emcyt®), sulindac, and etoposide.

In certain embodiments, the second active agent is etoposide,daunomycin, actinomycin D, mitomycin C, cisplatin, carboplatin,pemetrexed, methotrexate, Ara-C, 5-FU, wortmannin, gemcitabin,geldanamycin or a combination thereof.

In other embodiments, the second active agent is a supportive careagent. An example of supportive care agent is an antiemetic. Specificantiemetic agents include, but are not limited to, phenothiazines,butyrophenones, benzodiazapines, corticosteroids, serotonin antagonists,cannabinoids, and NK₁ receptor antagonists. Examples of phenothiazineantiemetics include, but are not limited to, prochlorperazine andtrimethobenzamide. Examples of butyophenone antiemetic include, but arenot limited to, haloperidol. Examples of benzodiazapine antiemeticinclude, but are not limited to, lorazepam. Examples of corticosteroidantiemetic include, but are not limited to, dexamethasone. Examples ofserotonin antagonist antiemetic include, but are not limited to,ondansetron, granisetron, and dolasetron. Examples of cannabinoidantiemetic include, but are not limited to, dronabinol. Examples of NK₁receptor antagonists include, but are not limited to, aprepitant. Dosesand dosing regimens of antiemetic agents should depend on the specificindication being treated, age and condition of a patient, and severityof adverse effects, and may be adjusted accordingly by those of skill inthe art. Examples of doses and dosing regimens can be found, forexample, in The Physician's Desk Reference.

6.5.2 Exemplary Methods of Combination Therapy

In certain embodiments, the methods provided herein compriseadministering SNS-595 in combination with one or more second activeagents, and/or in combination with radiation therapy or surgery. Theadministration of SNS-595 and the second active agents to a patient canoccur simultaneously or sequentially by the same or different routes ofadministration. The suitability of a particular route of administrationemployed for a particular active agent will depend on the active agentitself (e.g., whether it can be administered orally without decomposingprior to entering the blood stream) and the disease being treated.Recommended routes of administration for the second active agents areknown to those of ordinary skill in the art. See, e.g., Physicians' DeskReference (60^(th) ed., 2006).

In one embodiment, the second active agent is administered intravenouslyor subcutaneously and once or twice daily in an amount of from about 1to about 1,000 mg, from about 5 to about 500 mg, from about 10 to about375 mg or from about 50 to about 200 mg. In one embodiment, the secondactive agent is rituximab, oblimersen (Genasense®), GM-CSF, G-CSF, EPO,taxotere, irinotecan, dacarbazine, transretinoic acid, topotecan,pentoxifylline, ciprofloxacin, dexamethasone, vincristine, doxorubicin,COX-2 inhibitor, IL2, IL8, IL18, IFN, Ara-C, vinorelbine or acombination thereof. In certain embodiments, the second active agent isetoposide, daunomycin, actinomycin D, mitomycin C, cisplatin,carboplatin, pemetrexed, methotrexate, Ara-C, 5-FU, wortmannin,geldanamycin, gemcitabin or a combination thereof.

In another embodiment, provided herein are methods of treating,preventing and/or managing hematologic malignancies, which compriseadministering SNS-595 in conjunction with (e.g., before, during orafter) conventional therapy including, but not limited to, surgery,immunotherapy, biological therapy, radiation therapy or other non-drugbased therapy presently used to treat, prevent or manage cancer. Withoutbeing limited by theory, it is believed that SNS-595 may provideadditive or synergistic effects when given concurrently withconventional therapy.

In certain embodiments, the second active agent is co-administered withSNS-595 or administered with 1-50 hours delay. In certain embodiments,SNS-595 is administered first followed by administration with the secondactive agent with 1-50 hours delay. In other embodiments, the secondactive agent is administered first followed by administration of SNS-595with 1-50 hours delay. In some embodiment, the delay is 24 hours.

In one embodiment, SNS-595 can be administered in an amount of fromabout 1 to about 75 mg/m², 1 to about 60 mg/m², 1 to about 48 mg/m², 1to about 24 mg/m², 1 to about 50 mg/m², about 1 to about 40 mg/m², about1 to about 30 mg/m², about 3 to about 30 mg/m², about 3 to about 24mg/m² alone or in combination with a second active agent disclosedherein, prior to, during, or after the use of conventional therapy.

In another embodiment, the methods provided herein comprise: a)administering to a patient in need thereof, a dose of about 1 mg/m² to75 mg/m² of SNS-595 and b) administering a therapeutically effectiveamount of a supportive care agent.

In one embodiment, the second agent is an alkylating agent. In anotherembodiment, the alkylating agent is an alkyl sulfonate and the cancerbeing treated is leukemia or lymphoma. In another embodiment, the alkylsulfonate is busulfan. In another embodiment, the alkyl sulfonate isbusulfan and the therapeutically effective amount is a daily dose of atleast 1 mg. In another embodiment, the alkyl sulfonate is busulfan andthe therapeutically effective amount is a daily oral dose of betweenabout 2 mg and 8 mg. In another embodiment, the alkyl sulfonate isbusulfan and the therapeutically effective amount is a daily oral doseof between about 1 mg and about 3 mg.

In another embodiment, the alkylating agent is a nitrogen mustard andthe cancer being treated is bladder cancer, breast cancer, Hodgkin'sdisease, leukemia, lung cancer, melanoma, ovarian cancer, or testicularcancer. In another embodiment, the nitrogen mustard is chlorambucil. Inanother embodiment, the nitrogen mustard is chlorambucil and thetherapeutically effective amount is at least 0.1 mg/kg. In anotherembodiment, the nitrogen mustard is chlorambucil and the therapeuticallyeffective amount is a daily oral dose of between about 0.1 mg/kg andabout 0.2 mg/kg for three to six weeks. In another embodiment, thenitrogen mustard is chlorambucil and the therapeutically effectiveamount is a dose of 0.4 mg/kg every three to four weeks. In anotherembodiment, the nitrogen mustard is cyclophosphamide. In anotherembodiment, the nitrogen mustard is cyclophosphamide and thetherapeutically effective amount is an intravenous dose of at least 10mg/kg. In another embodiment, the nitrogen mustard is cyclophosphamideand the therapeutically effective amount is an intravenous dose betweenabout 10 mg/kg and about 15 mg/kg every seven to ten days. In anotherembodiment, the nitrogen mustard is cyclophosphamide and thetherapeutically effective amount is an oral daily dose between about 1mg/kg and about 5 mg/kg. In another embodiment, the nitrogen mustard ismelphalan. In another embodiment, the nitrogen mustard is melphalan andthe therapeutically effective amount is a daily oral dose of at least 2mg. In another embodiment, the nitrogen mustard is melphalan and thetherapeutically effective amount is a daily oral dose of 6 mg for two tothree weeks, no melphalan for two to four weeks and then a daily oraldose of between about 2 mg and about 4 mg. In another embodiment, thenitrogen mustard is melphalan and the therapeutically effective amountis a daily oral dose of 10 mg/m² for four days every four to six weeks.

In another embodiment, the alkylating agent is a nitrosourea and thecancer being treated is brain tumor, colorectal cancer, Hodgkin'sdisease, liver cancer, lung cancer, lymphoma, or melanoma. In anotherembodiment, the nitrosourea is carmustine. In another embodiment, thenitrosourea is carmustine and the therapeutically effective amount is atleast 150 mg/m². In another embodiment, the nitrosourea is carmustineand the therapeutically effective amount is an intravenous dose betweenabout 150 mg/m² and 200 mg/m² every six to eight weeks.

In another embodiment, the alkylating agent is a triazene and the cancerbeing treated is Hodgkin's disease, melanoma, neuroblastoma, or softtissue sarcoma. In another embodiment, the triazene is dacarbazine. Inanother embodiment, the triazene is dacarbazine and the therapeuticallyeffective amount is a daily intravenous dose of between about 2.0 mg/kgand about 4.5 mg/kg for ten days every four weeks. In anotherembodiment, the triazene is dacarbazine and the therapeuticallyeffective amount is a daily intravenous dose of 250 mg/m² for five daysevery three weeks. In another embodiment, the triazene is dacarbazineand the therapeutically effective amount is an intravenous dose of 375mg/m² every sixteen days. In another embodiment, the triazene isdacarbazine and the therapeutically effective amount is an intravenousdose of 150 mg/m² for five days every four weeks.

In another embodiment, the second agent is an anti-neoplastic antibioticand the cancer being treated is bladder cancer, breast cancer, cervicalcancer, head and neck cancer, Hodgkin's disease, leukemia, multiplemyeloma, neuroblastoma, ovarian cancer, sarcoma, skin cancer, testicularcancer, or thyroid cancer. In another embodiment, the antibiotic isbleomycin. In another embodiment, the antibiotic is bleomycin and thetherapeutically effective amount is at least 10 units/m². In anotherembodiment, the antibiotic is bleomycin and the therapeuticallyeffective amount is an intravenous, subcutaneous, or intramuscular doseof between about 10 units/m² and about 20 units/m² weekly or twiceweekly. In another embodiment, the antibiotic is dactinomycin. Inanother embodiment, the antibiotic is dactinomycin and thetherapeutically effective amount is at least 0.01 mg/kg. In anotherembodiment, the antibiotic is dactinomycin and the therapeuticallyeffective amount is a daily intravenous dose of between about 0.010mg/kg and about 0.015 mg/kg for five days every three weeks. In anotherembodiment, the antibiotic is dactinomycin and the therapeuticallyeffective amount is an intravenous dose of 2 mg/m² every three or fourweeks. In another embodiment, the antibiotic is daunorubicin. In anotherembodiment, the antibiotic is daunorubicin and the therapeuticallyeffective amount is at least 30 mg/m². In another embodiment, theantibiotic is daunorubicin and the therapeutically effective amount is adaily intravenous dose of between about 30 mg/m² and about 45 mg/m² forthree days. In another embodiment, the antibiotic is a liposomalpreparation of daunorubicin and the therapeutically effective amount isan intravenous dose of 40 mg/m² every two weeks. In another embodiment,the antibiotic is doxorubicin. In another embodiment, the antibiotic isdoxorubicin and the therapeutically effective amount is at least 15mg/m². In another embodiment, the antibiotic is doxorubicin and thetherapeutically effective amount is an intravenous dose of between about60 mg/m² and about 90 mg/m² every three weeks. In another embodiment,the antibiotic is doxorubicin and the therapeutically effective amountis a weekly intravenous dose of between about 15 mg/m² and about 20mg/m². In another embodiment, the antibiotic is doxorubicin and thetherapeutically effective amount is a cycle comprising a weeklyintravenous dose of 30 mg/m² for two weeks followed by two weeks of nodoxorubicin.

In another embodiment, the second agent is an anti-metabolite. Inanother embodiment, the anti-metabolite is a folate analog and thecancer being treated is breast cancer, head and neck cancer, leukemia,lung cancer, non-Hodgkin's lymphoma, or osteosarcoma. In anotherembodiment, the folate analog is methotrexate. In another embodiment,the folate analog is methotrexate and the therapeutically effectiveamount is at least 2.5 mg. In another embodiment, the folate analog ismethotrexate and the therapeutically effective amount is a daily oraldose of between about 2.5 mg and about 5 mg. In another embodiment, thefolate analog is methotrexate and the therapeutically effective amountis a twice-weekly dose of between about 5 mg/m² and about 25 mg/m². Inanother embodiment, the folate analog is methotrexate and thetherapeutically effective amount is a weekly intravenous dose of 50mg/m² every two to three weeks. In another embodiment, the folate analogis pemetrexed. In another embodiment, the folate analog is pemetrexedand the therapeutically effective amount is at least 300 mg/m². Inanother embodiment, the folate analog is pemetrexed and thetherapeutically effective amount is an intravenous dose of between about300 mg/m² and about 600 mg/m² every two or three weeks. In anotherembodiment, the folate analog is pemetrexed and the therapeuticallyeffective amount is an intravenous dose of 500 mg/m² every three weeks.

In another embodiment, the anti-metabolite is a purine analog and thecancer being treated is colorectal cancer, leukemia, or myeloma. Inanother embodiment, the purine analog is mercaptopurine. In anotherembodiment, the purine analog is mercaptopurine and the therapeuticallyeffective amount is at least 1.5 mg/kg. In another embodiment, thepurine analog is mercaptopurine and the therapeutically effective amountis a daily oral dose of between about 1.5 mg/kg and about 5 mg/kg. Inanother embodiment, the purine analog is thioguanidine. In anotherembodiment, the purine analog is thioguanidine and the therapeuticallyeffective amount is at least 2 mg/kg. In another embodiment, the purineanalog is thioguanidine and the therapeutically effective amount is adaily oral dose of between about 2 mg/kg and about 3 mg/kg.

In another embodiment, the anti-metabolite is an adenosine analog andthe cancer being treated is leukemia or lymphoma. In another embodiment,the adenosine analog is cladribine. In another embodiment, the adenosineanalog is cladribine and the therapeutically effective amount is atleast 0.09 mg/kg. In another embodiment, the adenosine analog iscladribine and the therapeutically effective amount is a dailyintravenous dose of 0.09 mg/kg for seven days. In another embodiment,the adenosine analog is cladribine and the therapeutically effectiveamount is a daily intravenous dose of 4 mg/m² for seven days. In anotherembodiment, the adenosine analog is pentostatin. In another embodiment,the adenosine analog is pentostatin and the therapeutically effectiveamount is 4 mg/m². In another embodiment, the adenosine analog ispentostatin and the therapeutically effective amount is an intravenousdose of 4 mg/m² every other week. In another embodiment, the adenosineanalog is pentostatin and the therapeutically effective amount is anintravenous dose of 4 mg/m² every three weeks.

In another embodiment, the anti-metabolite is a pyrimidine analog andthe cancer being treated is bladder cancer, breast cancer, colorectalcancer, esophageal cancer, head and neck cancer, leukemia, liver cancer,lymphoma, ovarian cancer, pancreatic cancer, skin cancer, or stomachcancer. In another embodiment, the pyrimidine analog is cytarabine. Inanother embodiment, the pyrimidine analog is cytarabine and thetherapeutically effective amount is at least 100 mg/m². In anotherembodiment the pyrimidine analog is cytarabine and the therapeuticallyeffective amount is a daily intravenous dose of 100 mg/m² for sevendays. In another embodiment, the pyrimidine analog is capecitabine. Inanother embodiment, the pyrimidine analog is capecitabine and thetherapeutically effective amount is at least a daily dose of 2000 mg/m².In another embodiment, they pyrimidine analog is capecitabine and thetherapeutically effective amount is a twice-daily oral dose of betweenabout 1200 mg/m² and about 1300 mg/m² for 14 days. In anotherembodiment, the pyrimidine analog is capecitabine and thetherapeutically effective amount is a three-week cycle wherein atwice-daily dose of about 1250 mg/m² is given for fourteen days followedby one week of rest. In another embodiment, the pyrimidine analog isfluorouracil. In another embodiment, the pyrimidine analog isfluorouracil and the therapeutically effective amount is at least 10mg/kg. In another example, the pyrimidine analog is fluorouracil and thetherapeutically effective amount is a daily intravenous dose of betweenabout 300 mg/m² and about 500 mg/m² for at least three days. In anotherexample, the pyrimidine analog is fluorouracil and the therapeuticallyeffective amount is a daily intravenous dose of 12 mg/kg for three tofive days. In another embodiment, the pyrimidine analog is fluorouraciland the therapeutically effective amount is a weekly intravenous dose ofbetween about 10 mg/kg and about 15 mg/kg.

In another embodiment, the anti-metabolite is a substituted urea and thecancer being treated is head and neck cancer, leukemia, melanoma, orovarian cancer. In another embodiment, the substituted urea ishydroxyurea. In another embodiment, the substituted urea is hydroxyureaand the therapeutically effective amount is at least 20 mg/kg. Inanother embodiment, the substituted urea is hydroxyurea and thetherapeutically effective amount is an oral dose of 80 mg/kg every threedays. In another embodiment, the substituted urea is hydroxyurea and thetherapeutically effective amount is a daily oral dose of between about20 mg/kg and about 30 mg/kg.

In another embodiment, the second agent is a platinum coordinationcomplex and the cancer being treated is bladder cancer, breast cancer,cervical cancer, colon cancer, head and neck cancer, leukemia, lungcancer, lymphoma, ovarian cancer, sarcoma, testicular cancer, or uterinecancer. In another embodiment, the platinum coordination complex iscarboplatin. In another embodiment, the platinum coordination complex iscarboplatin and the therapeutically effective amount is at least 300mg/m². In another embodiment, the platinum coordination complex iscarboplatin and the therapeutically effective amount is at least 300mg/m² every four weeks. In another embodiment, the platinum coordinationcomplex is carboplatin and the therapeutically effective amount is 300mg/m² every four weeks. In another embodiment, the platinum coordinationcomplex is carboplatin and the therapeutically effective amount is atleast 360 mg/m² every four weeks. In another embodiment, the platinumcoordination complex is cisplatin. In another embodiment, the platinumcoordination complex is cisplatin and the therapeutically effectiveamount is at least 20 mg/m². In another embodiment, the platinumcoordination complex is cisplatin and the therapeutically effectiveamount is a daily intravenous dose of 20 mg/m² for four to five daysevery three to four weeks. In another embodiment, the platinumcoordination complex is cisplatin and the therapeutically effectiveamount is an intravenous dose of 50 mg/m² every three weeks. In anotherembodiment, the platinum coordination complex is oxaliplatin. In anotherembodiment, the platinum coordination complex is oxaliplatin and thetherapeutically effective amount is at least 75 mg/m². In anotherembodiment, the platinum coordination complex is oxaliplatin and thetherapeutically effective amount is between about 50 mg/m² and about 100mg/m². In another embodiment, the platinum coordination complex isoxaliplatin and the therapeutically effective amount is an IV infusionof between about 50 mg/m² and about 100 mg/m² every two weeks. Inanother embodiment, the platinum coordination complex is oxaliplatin andthe therapeutically effective amount is an IV infusion of between about80 mg/m² and about 90 mg/m² every two weeks. In another embodiment, theplatinum coordination complex is oxaliplatin and the therapeuticallyeffective amount is a two-hour IV infusion of 85 mg/m² every two weeks.

In another embodiment, the second agent is a topoisomerase II inhibitorand the cancer being treated is Hodgkin's disease, leukemia, small celllung cancer, sarcoma, or testicular cancer. In another embodiment, thetopoisomerase II inhibitor is etoposide. In another embodiment, thetopoisomerase II inhibitor is etoposide and the therapeuticallyeffective amount is at least 35 mg/m². In another embodiment, thetopoisomerase II inhibitor is etoposide and the therapeuticallyeffective amount is between about 50 mg/m² and about 100 mg/m². Inanother embodiment, the topoisomerase II inhibitor is etoposide and thetherapeutically effective amount is an intravenous dose of between about35 mg/m² and about 50 mg/m² a day at least three times in five daysevery three or four weeks. In another embodiment, the topoisomerase IIinhibitor is etoposide and the therapeutically effective amount is anintravenous dose of between about 50 mg/m² and about 100 mg/m² a day atleast three times in five days every three or four weeks. In anotherembodiment, the topoisomerase II inhibitor is etoposide and thetherapeutically effective amount is an oral dose of 100 mg/m² a day atleast three times in five days every three or four weeks. In anotherembodiment, the topoisomerase II inhibitor is teniposide. In anotherembodiment, the topoisomerase II inhibitor is teniposide and thetherapeutically effective amount is at least 20 mg/m². In anotherembodiment, the topoisomerase II inhibitor is teniposide and thetherapeutically effective amount is a weekly dose of 100 mg/m². Inanother embodiment, the topoisomerase II inhibitor is teniposide and thetherapeutically effective amount is a twice weekly dose of 100 mg/m². Inanother embodiment, the topoisomerase II inhibitor is teniposide and thetherapeutically effective amount is a daily dose of between about 20mg/m² and about 60 mg/m² for five days. In another embodiment, thetopoisomerase II inhibitor is teniposide and the therapeuticallyeffective amount is a daily dose of between about 80 mg/m² and about 90mg/m² for five days.

6.6 Pharmaceutical Compositions and Dosage Forms

The methods provided herein use pharmaceutical compositions containingSNS-595 and pharmaceutically acceptable carriers, such as diluents oradjuvants, or in combination with other active ingredient, such asanother anti-cancer agent. In clinical practice SNS-595 may beadministered by any conventional route, including but not limited toorally, parenterally, rectally or by inhalation (e.g. in the form ofaerosols). In some embodiments, the compositions provided herein areacidic compositions (e.g., pH<4). Without being limited by a particulartheory, acidic compositions provide the appropriate balance of increasedsolubility of SNS-595 and desirable pharmaceutical properties (e.g.,increased patient comfort by causing less irritation at the deliverysite).

In one embodiment, SNS-595 is administered by an IV injection. Thecompositions for parenteral administration can be emulsions or sterilesolutions. Use may be made, as solvent or vehicle, of propylene glycol,a polyethylene glycol, vegetable oils, in particular olive oil, orinjectable organic esters, for example ethyl oleate. These compositionscan also contain adjuvants, in particular wetting, isotonizing,emulsifying, dispersing and stabilizing agents. Sterilization can becarried out in several ways, for example using a bacteriological filter,by radiation or by heating. They can also be prepared in the form ofsterile solid compositions which can be dissolved at the time of use insterile water or any other injectable sterile medium.

The compositions can also be aerosols. For use in the form of liquidaerosols, the compositions can be stable sterile solutions or solidcompositions dissolved at the time of use in apyrogenic sterile water,in saline or any other pharmaceutically acceptable vehicle. For use inthe form of dry aerosols intended to be directly inhaled, the activeprinciple is finely divided and combined with a water-soluble soliddiluent or vehicle, for example dextran, mannitol or lactose.

Pharmaceutical compositions can be used in the preparation ofindividual, single unit dosage forms. Pharmaceutical compositions anddosage forms comprise SNS-595 and one or more excipients.

Pharmaceutical compositions and dosage forms can also comprise one ormore additional active ingredients. Examples of optional second, oradditional, active ingredients are disclosed herein.

In certain embodiments, a composition provided herein is apharmaceutical composition or a single unit dosage form. Pharmaceuticalcompositions and single unit dosage forms provided herein comprise aprophylactically or therapeutically effective amount of SNS-595, andtypically one or more pharmaceutically acceptable carriers orexcipients. The term “carrier” refers to a diluent, adjuvant (e.g.,Freund's adjuvant (complete and incomplete)), excipient, or vehicle withwhich the therapeutic is administered. Such pharmaceutical carriers canbe sterile liquids, such as water and oils, including those ofpetroleum, animal, vegetable or synthetic origin, such as peanut oil,soybean oil, mineral oil, sesame oil and the like. In certainembodiments, water is a carrier when the pharmaceutical composition isadministered intravenously. Saline solutions and aqueous dextrose andglycerol solutions can also be employed as liquid carriers, particularlyfor injectable solutions. Examples of suitable pharmaceutical carriersare described in “Remington's Pharmaceutical Sciences” by E. W. Martin.

Typical pharmaceutical compositions and dosage forms comprise one ormore excipients. Suitable excipients are well-known to those skilled inthe art of pharmacy, and non limiting examples of suitable excipientsinclude starch, glucose, lactose, sucrose, gelatin, malt, rice, flour,chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodiumchloride, dried skim milk, glycerol, propylene, glycol, water, ethanoland the like. Whether a particular excipient is suitable forincorporation into a pharmaceutical composition or dosage form dependson a variety of factors well known in the art including, but not limitedto, the way in which the dosage form will be administered to a subjectand the specific active ingredients in the dosage form. The compositionor single unit dosage form, if desired, can also contain minor amountsof wetting or emulsifying agents, or pH buffering agents.

Further provided herein are pharmaceutical compositions and dosage formsthat comprise one or more compounds that reduce the rate by which anactive ingredient will decompose. Such compounds, which are referred toherein as “stabilizers,” include, but are not limited to, antioxidantssuch as ascorbic acid, pH buffers, or salt buffers.

The pharmaceutical compositions and single unit dosage forms can takethe form of solutions, suspensions, emulsion, powders and the like. Suchcompositions and dosage forms will contain a prophylactically ortherapeutically effective amount of a prophylactic or therapeutic agent,in certain embodiments, in purified form, together with a suitableamount of carrier so as to provide the form for proper administration tothe subject. The formulation should suit the mode of administration. Inone embodiment, the pharmaceutical compositions or single unit dosageforms are sterile and in suitable form for administration to a subject,such as an animal subject, or a mammalian subject, and such as a humansubject.

A pharmaceutical composition provided herein is formulated to becompatible with its intended route of administration. Examples of routesof administration include, but are not limited to, parenteral, e.g.,intravenous, intradermal, subcutaneous, intramuscular, subcutaneous,inhalation, intranasal, transdermal, topical, transmucosal,intra-tumoral, intra-synovial and rectal administration. In a specificembodiment, the composition is formulated in accordance with routineprocedures as a pharmaceutical composition adapted for intravenous,subcutaneous, intramuscular, intranasal or topical administration tohuman beings. In an embodiment, a pharmaceutical composition isformulated in accordance with routine procedures for subcutaneousadministration to human beings. Typically, compositions for intravenousadministration are solutions in sterile isotonic aqueous buffer. Wherenecessary, the composition may also include a solubilizing agent and alocal anesthetic such as lignocamne to ease pain at the site of theinjection.

Examples of dosage forms include, but are not limited to: liquid dosageforms suitable for parenteral administration to a subject; and sterilesolids (e.g., crystalline or amorphous solids) that can be reconstitutedto provide liquid dosage forms suitable for parenteral administration toa subject.

The composition, shape, and type of dosage forms provided herein willtypically vary depending on their use. For example, a dosage form usedin the initial treatment of disease may contain larger amounts of one ormore of the active ingredients it comprises than a dosage form used inthe maintenance treatment of the same infection. Similarly, a parenteraldosage form may contain smaller amounts of one or more of the activeingredients it comprises than an oral dosage form used to treat the samedisease or disorder. These and other ways in which specific dosage formsencompassed herein will vary from one another will be readily apparentto those skilled in the art. See, e.g., Remington's PharmaceuticalSciences, 20th ed., Mack Publishing, Easton Pa. (2000).

Generally, the ingredients of compositions provided herein are suppliedeither separately or mixed together in unit dosage form, for example, asa dry lyophilized powder or water free concentrate in a hermeticallysealed container such as an ampoule or sachette indicating the quantityof active agent. Where the composition is to be administered byinfusion, it can be dispensed with an infusion bottle containing sterilepharmaceutical grade water or saline. Where the composition isadministered by injection, an ampoule of sterile water for injection orsaline can be provided so that the ingredients may be mixed prior toadministration.

Typical dosage forms provided herein comprise SNS-595 within the rangeof about 1 mg/m² to about 75 mg/m² per day, or weekly, given as a singleonce-a-day dose in the morning or as divided doses throughout the daytaken with food. Particular dosage forms provided herein have about 1,3, 6, 9, 12, 15, 18, 21, 24, 27 or 30 mg/m² of SNS-595.

6.6.1 Parenteral Dosage Forms

Parenteral dosage forms can be administered to patients by variousroutes including, but not limited to, subcutaneous, intravenous(including bolus injection), intramuscular, and intraarterial. Becausetheir administration typically bypasses patients' natural defensesagainst contaminants, parenteral dosage forms are preferably sterile orcapable of being sterilized prior to administration to a patient.Examples of parenteral dosage forms include, but are not limited to,solutions ready for injection, dry products ready to be dissolved orsuspended in a pharmaceutically acceptable vehicle for injection,suspensions ready for injection, and emulsions.

Suitable vehicles that can be used to provide parenteral dosage formsare well known to those skilled in the art. Examples include, but arenot limited to: Water for Injection USP; aqueous vehicles such as, butnot limited to, Sodium Chloride Injection, Ringer's Injection, DextroseInjection, Dextrose and Sodium Chloride Injection, and Lactated Ringer'sInjection; water-miscible vehicles such as, but not limited to, ethylalcohol, polyethylene glycol, and polypropylene glycol; and non-aqueousvehicles such as, but not limited to, corn oil, cottonseed oil, peanutoil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

Compounds that increase the solubility of one or more of the activeingredients disclosed herein can also be incorporated into theparenteral dosage forms. For example, cyclodextrin and its derivativescan be used to increase the solubility of active ingredients. See, e.g.,U.S. Pat. No. 5,134,127, which is incorporated herein by reference.

6.6.2 Topical and Mucosal Dosage Forms

In certain embodiments, provided herein are transdermal, topical, andmucosal dosage forms. Transdermal, topical, and mucosal dosage formsprovided herein include, but are not limited to, ophthalmic solutions,sprays, aerosols, creams, lotions, ointments, gels, solutions,emulsions, suspensions, or other forms known to one of skill in the art.See, e.g., Remington's Pharmaceutical Sciences, 20th ed., MackPublishing, Easton Pa. (2000); and Introduction to Pharmaceutical DosageForms, 4th ed., Lea & Febiger, Philadelphia (1985). Dosage formssuitable for treating mucosal tissues within the oral cavity can beformulated as mouthwashes or as oral gels. Further, transdermal dosageforms include “reservoir type” or “matrix type” patches, which can beapplied to the skin and worn for a specific period of time to permit thepenetration of a desired amount of active ingredients.

Suitable excipients (e.g., carriers and diluents) and other materialsthat can be used to provide topical and mucosal dosage forms encompassedherein are well known to those skilled in the pharmaceutical arts, anddepend on the particular tissue to which a given pharmaceuticalcomposition or dosage form will be applied. With that fact in mind,typical excipients include, but are not limited to, water, acetone,ethanol, ethylene glycol, propylene glycol, butane-1,3-diol, isopropylmyristate, isopropyl palmitate, mineral oil, and mixtures thereof toform solutions, emulsions or gels, which are non-toxic andpharmaceutically acceptable. Moisturizers or humectants can also beadded to pharmaceutical compositions and dosage forms if desired.Examples of such additional ingredients are well known in the art. See,e.g., Remington's Pharmaceutical Sciences, 20th ed., Mack Publishing,Easton Pa. (2000).

The pH of a pharmaceutical composition or dosage form may also beadjusted to improve delivery of one or more active ingredients.Similarly, the polarity of a solvent carrier, its ionic strength, ortonicity can be adjusted to improve delivery. Compounds such asstearates can also be added to pharmaceutical compositions or dosageforms to advantageously alter the hydrophilicity or lipophilicity of oneor more active ingredients so as to improve delivery. In this regard,stearates can serve as a lipid vehicle for the formulation, as anemulsifying agent or surfactant, and as a delivery-enhancing orpenetration-enhancing agent. Different salts, hydrates or solvates ofthe active ingredients can be used to further adjust the properties ofthe resulting composition.

7. EXAMPLES

Certain embodiments provided herein are illustrated by the followingnon-limiting example.

Example 1 Pharmaceutical Composition Suitable for Injection orIntravenous Infusion

Acidic compositions (<pH 4) provided the appropriate balance ofincreased solubility of SNS-595 and desirable pharmaceutical properties(e.g. increased patient comfort by causing less irritation at thedelivery site). An illustrative example of a suitable compositioncomprises: 10 mg SNS-595 per mL of aqueous solution of 4.5% sorbitolthat is adjusted to pH 2.5 with methanesulfonic acid. One protocol formaking such a solution includes the following for making a 100 mg/10 mLpresentation: 100 mg of SNS-595 and 450 mg D-sorbitol are added todistilled water; the volume is brought up to a volume of 10 mL; and thepH of the resulting solution is adjusted to 2.5 with methanesulfonicacid. The resulting composition is also suitable for lyophilization. Thelyophilized form is then reconstituted with sterile water to theappropriate concentration prior to use.

Example 2 Clinical Trial Data of SNS-595 in Patients with Advanced SolidTumor Cancer

The safety and efficacy of SNS-595 were investigated in twodose-escalating studies. As demonstrated below, SNS-595 provides goodsafety profiles and evidence of anti-tumor activity in patients withrefractory solid tumors.

SNS-595 was administered to patients with advanced solid cancers as anIV infusion over 10 minutes on 2 schedules. In the first schedule (A), aweekly dose of SNS-595 was administered for three weeks followed by atleast 7 days off (qwk×3). In the second schedule (B), a dose of SNS-595was administered once every three weeks (q3wk).

In both schedules, the starting dose of SNS-595 was 3 mg/m², and doseswere escalated by sequential cohorts of 3. The doses were doubled untilthe first related adverse event at or above Grade 2 or until the firstabnormal lab value. The doses were then escalated by a modifiedFibonacci schema.

No other therapy, for example mitomycin-C, BCNU, nitrosourea drugs orMAb therapy, was given within 42 days of the study.

In study A, 21 patients (9 male, 12 female) were treated in 6 cohorts(dose range 3-24 mg/m²/wk). In study B, 41 (25 male, 16 female) patientswere treated in 9 cohorts (dose range 3-75 mg/m²/wk). The median ageswere 61 yrs (Study A) and 59 yrs (Study B), sex 12F/9M (Study A),16F/25M (Study B), all patients had baseline European CooperativeOncology Group Performance Status (ECOG PS) 0-2. Patient eligibilityincluded refractory solid tumors and adequate organ function. Table 1provides patient demographics in both the studies.

TABLE 1 Patient demographics qwk x3 q3wk total n (# treated) 21 41 62Sex Male 9 (43%) 25 (61%) 34 (55%) Female 12 (57%) 16 (39%) 28 (45%)Ethnic Background Asian 2 (10%) 1 (2%) 3 (5%) Black 2 (10%) 4 (10%) 6(10%) Hispanic 0 1 (2%) 1 (2%) Native Hawaiian/ 0 2 (5%) 2 (3%) PacificIslander White 17 (81%) 33 (81%) 50 (81%) Age (yrs) Mean 59.3 58.5 58.8Median 61 59 60 Range 19-81 33-79 19-81 Previous Therapies MP 9 (43%) 17(41%) 26 (42%) HP 12 (57%) 24 (59%) 36 (58%)

Table 2 provides a list of tumor types treated in both the studies.

TABLE 2 Tumor types treated qwk x3 q3wk total n (# treated) 21 41 62Ovarian 1 9 10 Colon 3 6 9 NSCLC 0 6 6 Pancreas 3 2 5 Renal 1 4 5Melanoma 1 3 4 Adeno CA (origin unk) 0 3 3 Breast 2 0 2 Sarcomas 0 3 3Cholangiocarcinoma 1 1 2 Mesothelioma 2 0 2 Neuroendocrine 1 1 2 Bladder0 1 1 Leiomyosarcoma 1 1 2 Liposarcoma 1 0 1 Müllerian 0 1 1Nasopharyngeal 1 0 1 Salivary Gland 1 0 1 Small Cell Lung Cancer 1 0 1Spindle Cell Carcinoma 1 0 1

For patients dosed according to schedule A, PK samples were collected ontreatment Days 1 and 15 and were assayed using noncompartmentalanalysis. Plasma SNS-595 concentrations were determined using avalidated LC-MS/MS assay. AUC (area under curve) increasedproportionally with dose and mean AUC_(Inf) and ranged between 1.7 and15 μg*hr/ml, respectively, for 3 to 24 mg/m² dose levels. The terminalhalf-life is approximately 19 hours. No evidence of drug dependentalterations in pharmacokinetic parameters was observed after 3 weeklydoses. FIG. 1 depicts the plasma concentrations of SNS-595 over timeamong the various patient cohorts. Table 3 provides the pharmacokineticparameters for patents dosed according to schedule A.

TABLE 3 Average of Week 1 and Week 3 Pharmacokinetic Parameters Dose n(Week 1, C_(max) AUC_(inf) Cl_(obs) V_(asobs) (mg/m²) Week 3) T½ hrμg/ml μg · hr/ml L/hrm² L/m²  3 7 23.3 ± 7.2 0.577 ± 0.795 1.71 ± 0.201.77 ± 0.23 52.7 ± 18.2 (4, 3)  6 6 13.5 ± 2.2 0.531 ± 0.28  2.09 ± 0.533.05 ± 0.84 51.0 ± 8.22 (3, 3) 12 6 19.9 ± 5.3 1.84 ± 2.7  6.81 ± 1.681.87 ± 0.53 44.6 ± 8.53 (3, 3) 15 10   26.4 ± 15.2 0.865 ± 0.318 10.8 ±4.7  1.59 ± 0.56 43.8 ± 7.90 (5, 5) 18 6 15.8 ± 4.2 1.69 ± 0.83 8.50 ±2.86 2.36 ± 0.88 47.19 ± 8.06  (4, 2) 24 1 24.2 0.6 15.2 1.58 50.0 (1,0) Average 18.5 ± 4.6 — — 2.22 ± 0.58 47.6 ± 10.7 Range 10-33 0.6-1.82-15 1.4-4.3 30-75

For patients dosed according to schedule B, pharmacokinetic parameterswere evaluated in 36 patients (21 heavily pretreated and 15 minimallypretreated) after a single dose of 3 to 75 mg/m². Clearance (CL), volumeof distribution, and terminal half-life (T_(1/2)) remained unchangedacross all patients up to 48 mg/m². In minimally pretreated patients, PKparameters remained unchanged up to 75 mg/m². CL was 2.2 L/hr/m2 (rangeof 1.0-3.8 L/hr/m²), the volume of distribution was 53 L/m² (range of31-76 L/m²), and the T_(1/2) was approximately 21 hr (range of 13-49hr). Exposure was similar for both heavily and minimally pretreatedpatients and increased linearly with doses up to 48 mg/m². Exposure forminimally pretreated patients showed a greater than dose linear AUC(area under the curve) at the 60 mg/m² dose level. Table 4 showspharmacokinetic parameters for patients dosed according to schedule B.

TABLE 4 Week 3 Pharmacokinetic Parameters Dose C_(max) AUC_(inf)Cl_(obs) V_(ssobs) (mg/m²) n T½ hr μg/ml μg · hr/ml L/hrm² L/m²  3 316.4 ± 4.8 0.139 ± 0.08  1.14 ± 0.26 2.72 ± 0.58 57.7 ± 8.7  6 2 22.2 ±1.9 0.347 ± 0.22  3.04 ± 0.32 1.98 ± 0.21 59.8 ± 0.5 12 3 18.0 ± 4.12.25 ± 1.07 6.32 ± 0.22 1.90 ± 0.07 45.2 ± 8.9 24 3 15.7 ± 3.2 2.70 ±2.57 12.63 ± 0.86  1.91 ± 0.13 40.7 ± 8.8 36 6 22.5 ± 4.2 3.38 ± 1.9218.05 ± 0.73  2.00 ± 0.08  61.4 ± 12.8 48 10  26.4 ± 13.1 3.08 ± 1.9229.41 ± 11.34 1.92 ± 0.91  58.8 ± 14.5 60 8  25.0 ± 17.9 3.86 ± 1.6840.71 ± 23.67 1.88 ± 0.88 48.0 ± 7.3 75 4 25.0 ± 4.9 5.05 ± 1.72 46.09 ±6.12  1.65 ± 0.22 56.3 ± 9.4 Average 21.3 ± 5.3 — — 2.0 ± 0.4 53.2 ± 4.1Range 13-56 0.1-5 1-46 1-3.8 31-76

In study A, pharmacokinetics were assessed on Days 1 and 15 (after thefirst and third doses). As seen in Table 5, SNS-595 shows highlyreproducible pharmacokinetics and low inter-patient variability. Noaccumulation or change in pharmacokinetic parameters was observed afterrepeat dosing. Exposure increased linearly over an 8-fold dose range(1.6-15 μg·hr/mL), clearance (CL), volume of distribution (Vss) andT_(1/2) averaged 2 L/hr/m², 48 L/m², 19 hr, respectively, and did notchange from Day 1 to 15.

In study B, pharmacokinetics were assessed on Day 1 after the firstdose; exposure increased linearly over the 24-fold dose range (1.1-46μg·hr/mL), CL, Vss, and T_(1/2) averaged 2 L/hr/m², 53 L/m², and 21 hrs,respectively.

Average pharmacokinetic parameters are provided for both studies inTable 5.

TABLE 5 Average of wk 1 and wk 3 Pharmacokinetic Parameters qwk x3, qwkx3, Week 1 Week 3 q3wk n 20 16 39 Dose Range (mg/m²) 3-24 3-18 3-75AUCinf Range 2-15 2-7  1-46 (μg · hr/mL) T_(1/2) (hr) ± SD 22 ± 11 19 ±8 21 ± 5 Clobs (L/hr/m2) ± SD 1.9 ± 0.7  2.2 ± 0.9  2.0 ± 0.4 Vss (L/m2)± SD 48 ± 12 47 ± 8 53 ± 4

FIG. 11 demonstrates dose linearity in Studies A and B.

Table 6 provides data for hematologic effects observed in the studies.

TABLE 6 Hematologic Effects # # ANC ≦ Febrile Dose Schedule n 500 Neut. 3 mg/m² qwk x3 4 0 0  6 mg/m² qwk x3 3 0 0 12 mg/m² qwk x3 3 0 0 15mg/m² qwk x3 6 0 0 18 mg/m² qwk x3 4 0 0 24 mg/m² qwk x3 1 0 0  3 mg/m²q3wk 3 0 0  6 mg/m² q3wk 3 0 0 12 mg/m² q3wk 3 0 0 24 mg/m² q3wk 3 0 036 mg/m² q3wk 6 0 0 48 mg/m² q3wk 6 1 0 48 mg/m² (HP) q3wk 5 2 0 60mg/m² q3wk 8 3 1 75 mg/m² q3wk 4 0 0 n = number of patients in cohort*Absolute Neutrophil Count (cells/μL) ≦500 lasting more than 7 days

In the description herein, the term “maximum tolerated dose” or “MTD”refers to the dose level below a dose of SNS-595 where ≧2 of 6 patientsexperienced dose limiting toxicity (DLT). The term, “heavily pretreated”or “HP” patient refers to a patient who has previously received >6courses of an alkylating agent, chemotherapy or >2 courses of platinum,mitomycin-C or any nitrosourea, or XRT to >25% of bone. The term,“minimally pretreated” or “MP” patient refers to a patient who does notfulfill the HP definition. (See, Tolcher et al, JCO 2001; 19:2937-2947).

As used herein, dose limiting toxicity (DLT) refers to absoluteneutrophil count (ANC)≦500 for ≧7 days or febrile neutropenia orplatelet nadir <25000 or bleeding or non-hematologic adverse events(AE)≧Grade 3 (as described in Common Terminology Criteria for AdverseEvents Version 3.0 (CTCAE v3.0)), wherein adverse events required >14days dose delay.

Tables 7-9 provide safety data for both the studies.

TABLE 7 Frequent (>10% patients) adverse events Body System preferredqwk x3 q3wk total term n = 21 n = 41 n = 62 Cardiac Disorders edema 0/4* peripheral Gastrointestina Disorders abd pain 1/5 0/8 1/13 (8%)constipation 0/7  1/12 1/19 (5%) diarrhea 0/4 0/8 0/12 (0%) nausea 0/8 2/26 2/34 (6%) vomiting 0/5  1/17 1/22 (5%) General Conditions fatigue1/4  1/13  2/17 (12%) Metabolism & Nutrition Disorders anorexia 0/7  0/7(0%) Musculoskeletal & Connective Tissue Disorders backpain 0/7  0/7(0%) pain in 0/5 extremity Nervous System Disorders dizziness 0/6  0/6(0%) headache 0/3 0/8 0/11 (0%) Skin & Subcutaneous Tissue Disordersalopecia 0/8  0/8 (0%) *no. patients with Grade ≧3/no. patients with anyGrade

TABLE 8 Hematologic Effects Qwk x3 q3wk total n = 21 n = 41 n = 62 Grade4 0 10 (24%) 10 (16%) Neutropenia (ANC <500/mm³) Febrile 0 1 (2%) 1 (2%)Neutropenia Grade 4 0 2 (5%) 2 (3%) Thrombocytopenia (<25,000/mm³)

TABLE 9 Serious Adverse Events (SAE) Possibly Related to Study Drug SAEpreferred term 1 patient for each CTCAE v3.0 Grade of the following qwkx3 q3wk Sepsis not Grade 3 observed Vomiting not Grade 3 observedPneumonia not Grade 3 observed Febrile not Grade 2 Neutropenia observedPancytopenia not Grade 4 observed Thrombosis not Grade 2 observed

As seen from the data, neutropenia was the dose limiting toxicity (DLT)for both studies. In study A, the dose-limiting toxicity (DLT) ofneutropenia was seen in the first patient at the 24 mg/m² level. 5patients were then treated at 18 mg/m² where 2 developed DLT ofneutropenia. In study B, for the heavily pretreated patients, the doselimiting toxicity (DLT) consisting of Grade 4 neutropenia for greaterthan 7 days was observed at 60 mg/m². For minimally pretreated patients,one dose limiting toxicity was seen at a dose of 75 mg/m².

The MTD for study A was 15 mg/m²; the MTD for study B was 48 mg/m² forheavily pretreated (HP) patients and 60 mg/m² for minimally pretreated(MP) patients.

For both studies two patients had grade 4 thrombocytopenia;non-hematologic toxicities were mostly grade 1/2 without dose-limitinggastrointestinal toxicity or neurotoxicity.

Table 10 provides evidence of clinical activity of SNS-595 for both thestudies. For study A, best responses included one patient that achievedpartial response (PR) and six that achieved stable disease SD (range16-24 wks). For study B, best responses included one PR and 11 SD (range18-58 wks). Table 11 provides details of Partial/Minor Responses (PR/MR)in both the studies.

TABLE 10 Evidence of Clinical Activity Initial Weeks Dosage Tumor onBest (mg/m²) Scheduled Type Therapy Response 6 qwk x3 Renal Cell 16 SD12 qwk x3 Leiomyosarcoma 16 SD Melanoma 16 SD 15 qwk x3 Mesothelioma 28PR Mesothelioma 18 SD Nasopharyngeal 16 SD 24 qwk x3 Salivary Gland 24SD 3 q3wk Lung 18 SD 6 q3wk Renal Cell 18 SD 12 q3wk Lung 53 SD 24 q3wkAdenocarcinoma 18 SD (unknown origin) 36 q3wk Ovarian 18 SD Colon 33 SD48 q3wk Ovarian 24 PR Ovarian 30 SD Lung 46 SD 60 q3wk Ovarian 33 SDNeuroendocrine 58 SD 75 q3wk Müllerian 46 SD

TABLE 11 Details of Partial/Minor Responses (PR/MR) Best Response TumorCriterion Baseline C2 C4 C6 PR Ovarian CA125 (U/mL) 467 272 176 120P-aortic node (cm) 1.7 1.6 1.5 1.3 Aortic node (cm) 2.4 2.0 2.2 2.0Iliac node (cm) 5.5 5.0 4.7 3.9 SD (MR) Nasopharyngeal Rt upper lobe 2.31.5 — — nodule 1 (cm) Rt upper lobe 1.5 1.3 — — nodule 2 (cm) Left upperlobe 1.1 1.0 — — nodule (cm) Lingular nodule 1.6 1.5 — — SD (MR) OvarianCA125 (U/mL) 567 811 419 274 Liver met (cm) 7.4 6.9 5.7 5.7 Aortic node(cm) 1.7 1.5 1.2 1.8 P-aortic node (cm) 1.8 1.1 1.1 1.2 SD (MR) OvarianCA125 (U/mL) 50 18 16 15 Rectosigmoid 2.5 0.0 0.0 0.0 (cm) 3 metsunchanged SD (MR) Mullerian RML Lung (cm) 3.9 3.9 3.7 2.4 RUL Lung (cm)4.7 4.5 4.5 5.0 RMLL Lung (cm) 2.5 2.5 2.5 2.6

Significantly, SNS-595 shows evidence of clinical activity in patientswith advanced solid cancers including two patients that achieved partialresponses and seventeen patients that achieved stable disease for oversixteen weeks.

As seen from the data, SNS-595 was well tolerated and showed clinicalactivity with both once a week and once three weeks dosing. The doselimiting toxicity was non-cumulative neutropenia. SNS-595 demonstratedpredictable pharmacokinetics with low inter- and intra patientvariability. No change in pharmacokinetic parameters was observed afterrepeat dosing.

Useful doses for treatment of solid tumors in patients in need thereofinclude 48 mg/m² once in three weeks and 15 mg/m² weekly as described inthis example.

Example 3 High Content Screening and Microscopy

Cells were plated as sub-confluent populations and allowed to grow for36 hours. Cells were then treated with the compound at the givenconcentration for the given time period. Cells were fixed using 4%formaldehyde and permeabilized with 0.1% triton. Cells were exposed toprimary antibodies for 1 hour at 25° C. at a 1:100 dilution in 10%FBS/PBS (anti-pATM—Chemicon, anti-gH2AX-Cell Signaling Technology).Cells were exposed to secondary antibodies for 1 hour at 25° C. at a1:100 dilution in 10% FBS/PBS. Hoechst staining was carried out in 10%FBS/PBS at 500 ng/ml concentrations. High content screening was carriedout on a Cellomics Arrayscan instrument using the Spot Detectoralgorithm.

FIG. 2 shows HCT116 cells that were dosed with various compounds for 6hour time periods. Cells were then fixed and analyzed for proteinphosphorylation state (gH2AX images obtained using a fluorescencemicroscope, pATM images obtained with the ArrayScan VTi). As seen in thefigure, SNS-595 treatment leads to nuclear foci formation.

FIGS. 3-5 illustrate dependence of foci formation on dose and time.Cells were then fixed and analyzed for phospho-ATM. Cellomics Arrayscansoftware was used to identify foci (FIG. 3, orange spots). Fociquantitation was carried out by measuring either foci fluorescentintensity (FIG. 4) or cells with more than 2 foci (FIG. 5) as a functionof time and SNS-595 concentration.

Example 4 MTT Assay and Sensitization Treatments

Cells were plated at 4000 cells per well in a 96 well plate, incubatedfor 24 hours and then treated with compound for 72 hours. Cells werethen incubated with 5% MTT for 1-2 hours and lysed. MTT wascolorimetrically read at 570 nm and EC₅₀'s were determined using linearregression analysis.

Sensitization was carried out with various chemical treatments. Cellswere pre-treated for 16 hours with chemical sensitizer before additionof drug (concentrations were as follows: caffeine, 2 mM, DNAPK inhibitorII (make), 10 uM, and wortmannin, 100 nM. Data is provided in Table 12.Sensitization was measured as the fold decrease in the EC₅₀ forcytotoxicity as measured by an MTT assay.

TABLE 12 DNA damage sensor dependence of SNS-595 Timing of Compound DSBMechanism ATRFLOX¹ DNAPKcs(−/−)² Caffeine³ Cell Line G2 Arrest⁴ S-Lag⁵apoptosis⁶ SNS-595 Replication 1 10 0.5 HCT-116 + + 0.4 dependentEtoposide Topoisomerase II 1 7 8 ATRFLOX¹ + + 0.35 Bleomycin Chemical 14 10 DNAPKcs(−/−)² + + 0.25 Camptothecin Topoisomerase I 5 0.7 6Caffeine³ − + 0.25 Replication dependent ¹HCT-116 cells with 6 foldlower ATR levels. ²MO59J (DNAPKcs(−/−)) vs MO59K (DNAPKcs(+/+)).³HCT-116 cells treated with 2 mM caffeine to disrupt both ATM and ATRkinase activities. ⁴FACS analysis, asynchronous cell population. ⁵FACSanalysis, synchronous cell population. ⁶Fraction of cell cycle toachieve 50% maximal caspase-3 activation if dosed at 30 fold above theEC50 for cytotoxicity.

The data indicates that SNS-595 displays a unique PIKK dependence. Whileboth ATM/ATR and DNAPK are activated following treatment with SNS-595,only DNAPK is required for DNA repair and cells are sensitized toSNS-595 only when DNAPKcs activity is diminished. ATM/ATR mediates aG2-checkpoint arrest. Loss of the G2-checkpoint does not sensitize cellsto SNS-595. In contrast to SNS-595, all other DSB-inducing agents testedutilize ATM/ATR for repair, and display sensitization when either ATM orDNAPK activities are inhibited.

Example 5 Repair of DNA Damage in the Absence of DNA-Damage SensingKinases ATM and ATR

HCT-116 cells were treated with 10 mM SNS-595 or 10 mM etoposide for 6 hwith or without 2 mM caffeine. Compound was then removed and cells wereallowed to recover for 16 hours. Cells were analyzed for gH2AX focibefore and after drug washout. As seen in FIG. 6, DNA damage induced bySNS-595 is readily repaired in the absence of ATM and ATR. In contrast,other drugs, (e.g. Etoposide), utilize ATM and ATR for DNA repair.Caffeine treatment inhibits the activities of ATM and ATR, leading todefects in homologous recombination, nucleotide excision repair, andmismatch repair.

Example 6 Repair of DNA Damage in the Absence of DNA-Damage SensingKinase DNA-PK

MO59K (wt) and MO59J (DNAPKcs(−/−)) cells were treated with 10 mMSNS-595 or 10 mM etoposide for 6 hours. Compound was then removed andcells were allowed to recover for 16 hours. Cells were analyzed forgH2AX foci before and after drug washout. As seen in FIG. 7, SNS-595damage is not effectively repaired in the absence of DNA-PK. Bycomparison, damage induced by other drugs (e.g. Etoposide), is readilyrepaired.

Example 7 Combination Studies with SNS-595

Cell lines and Cell Culture: HCT116 and NCI-H460 cell lines wereobtained from ATCC. SKOV3(p53−/−) and SKOV3(p53+/+) were obtained fromthe lab of Dr. George Stark of the Lerner Institute of the ClevelandClinic. All cell lines were cultured in RPMI media supplemented with 10%FBS 1% Sodium Bicarbonate solution and 1% Antibiotic Solution (Cellgro).

MTT assay: Cells were plated at 4000 cells per well (except SKOV3(p53−/−) which were plated at 8000 cells per well) in a 96 well plate,incubated for 24 hours and then treated with compound. Compoundtreatment lasted 72 hours. Cells were then incubated with 5% MTT for 1-2hours, and lysed. MTT was colorimetrically read at 570 nm. The fractionof dead cells was determined by the following formula:

Fraction of Dead cells=1−[Abs of sample well−Avg(Abs of no cellcontrol)]/[Avg(Abs of DMSO only control)−Avg(bs of no cell control)]

Scheduling studies: When compounds were dosed with a schedule thatincluded a washout, cells were washed with 100 μl of fresh warm mediafor 30 minutes, followed by another wash after 90 minutes.

Statistical Analysis: The data (Fraction of Dead cells) was analyzedusing Calculsyn.V2 (Biosoft) and is herein represented as the value ofthe Combination Index at Fraction affected (Fa)=0.5. All data is shownwith error bars indicating the 95% confidence intervals of the meanvalue.

A combination is said to be additive if it yields a Combination Index of0.85-1.2. A combination is said to be synergistic if it yields aCombination Index less than 0.85 and a combination is said to beantagonistic if it yields a Combination Index of more than 1.2. SeeFIGS. 8-10.

As seen in FIGS. 8 a-8 d, SNS-595 dosed simultaneously with variouscytotoxics in HCT116 colon carcinoma cell line (8 a, 8 b and 8 c) andH460 lung cancer cell line 8(d) showed significantly synergistic or atleast additive combination indices. As seen in FIG. 9, SNS-595 dosedsimultaneously with a selection of DNA damaging agents andantimetabolites showed no significant change in the combination indexbetween SKOV3 ovarian cancer cell line with or without p53 expression.

As seen in FIGS. 10 a-10 d, SNS-595 might have been antagonistic whenSNS-595 was co-dosed, or dosed with 24 hours delay, with docetaxel (see,FIGS. 10 a and 10 c) and gemcitabin (see, FIGS. 10 b and 10 d) in HCT116colon carcinoma cells. Antagonism might have been reduced by dosingSNS-595 first (see, FIGS. 10 c and 10 d, co-dose and 24 hrs) versusdosing the other agents first (see, FIGS. 10 a and 10 b, co-dose and 24hrs). Additivity or possibly synergy was achieved when cells weretreated with the first agent, washed and then treated with the secondagent (see, FIGS. 10 a-d, 2 hr wash and 24 hr wash).

Example 8 MTT Cell Viability Assay-Leukemia Cells

The following cell lines were used in this assay: HL-60 (promyelocyticleukemia); Jurkat (T cell leukemia); CCRF-CEM (lymphoblastic leukemia);CEM/C2 (camptothecan resistant derivative of CCRF-CEM).

Cells were seeded in 96 wells plates at 3000 cells per well andincubated for 16 hours. Compound dilutions were performed in DMSO from10 mM with 3 fold dilutions. Titrations were diluted 1:100 in media toachieve final compound concentrations. The 96 well plates were aspiratedand compound dilutions in media were added (100 ml/well). MTT analysiswas carried out after 72 hours of incubation at 37° C. Briefly, 20 ml ofMTT solution was added to each well. Cells were incubated at 37° C. for1-2 hours. Cells were lysed with the addition of 100 ml/well cell lysisbuffer and MTT was solubilized overnight at 37° C. Plates were read on aspectromax machine with an absorbance measurement at 570 nM. IC₅₀'s werecalculated (data provided in Table 13) using regression analysis withinGraphPad Prism. As provided in Table 13, SNS-595 shows potentanti-proliferative activity against hematologic cell lines tested.

TABLE 13 IC₅₀ data for various cell lines IC₅₀ ng/mL Cell Line SNS-595Etoposide Doxorubicin Irinotecan HL-60 53 136 24 905 Jurkat 23 nd Nd ndCCRF-CEM 18 nd  3 479 CEM/C2 10 nd 17 44400 

Example 9 Xenograft Models

LM3-Jck human malignant lymphoma tumor lobes (2-3 mm square) weretransplanted subcutaneously into nude mice. Tumors were allowed to growto approximately 7-14 mm in diameter. Mice were pair-matched into notreatment, irinotecan (100 mg/kg, IV, q4d×3), doxorubicin (12 mg/kg, IV,Single shot), etoposide (12 mg/kg, IV, q1d×5), and SNS-595 (25 and 20mg/kg, IV, q7d×5) treatment groups. Acceptable toxicity was defined as amean group weight loss of 30% or less and not more than one toxic deathamong 6 treated animals. Anti-tumor activities of the drugs wereassessed 21 days after the start of administration.

CCRF-CEM acute lymphoblastic leukemia tumor lobes of 2-3 mm square weretransplanted subcutaneously into nude mice. Tumors were allowed to growto approximately 8-20 mm in diameter. Mice were pair-matched into notreatment, irinotecan (100 mg/kg, IV, q4d×3), doxorubicin (12 mg/kg, IV,q7d×3), etoposide (12 mg/kg, IV, q1d×5), and SNS-595 (25 and 20 mg/kg,IV, q7d×5) treatment groups. Acceptable toxicity was defined as a meangroup weight loss of 30% or less and not more than one toxic death among6 treated animals. Anti-tumor activities of the drugs were assessed 20or 21 days after the start of administration. Table 14 provides data fortumor inhibition (TI) and survival rate in the CCRF-CEM and LM3-Jckxenograft models.

TABLE 14 Comparative anti-tumor activity of SNS-595 and otheranti-cancer drugs CCRF-CEM LM3 - JcK Dose IR Survival IR SurvivalTreatment (mg/kg) (%) Ratio (%) Ratio SNS-595 q7d X3, IV 20 —* — 98.9*6/6 25 98.1*  6/6* 98.5* 6/6 Irinotecan q4d x3, IV 100 99.7* 5/6 97.7*6/6 Doxorubicin q7d X3, IV 12 50.3* 6/6 57.2* 6/6 Etoposide qd X 5, IV12 28.3  6/6 3.0 6/6

As seen from the data in Table 14, SNS-595 administered at 20 and 25mg/kg shows strong antitumor activity with complete tumor regressionsagainst LM-3 Jck malignant lymphoma. Tumor inhibition rate (IR) ofSNS-595 was similar to that of irinotecan and superior to etoposide anddoxorubicin in both the CCRF-CEM and LM3-Jck xenograft models.

Example 10 Bone Marrow/Cytology Assay

Female CD-1 mice were administered 5, 10, 15, or 20 mg/kg SNS-595intravenously on Day 0 and Day 4. Blood was drawn on days 6, 8, and 12post initial injection for hematological analysis. Femurs were extractedon day 6 fixed in Streck and H&E stained prior to bone marrowcellularity analysis. Two days after the second administration ofSNS-595, bone marrow isolated from femurs showed a dose-dependentreduction in cellularity. At 20 mg/kg, cellularity was reduced to 7.5%,while circulating neutrophils were reduced from a pre-dose level of1244±55 cells/mL to a nadir of 51±24 cells/mL blood on day 8. Absoluteneutrophil counts subsequently rebounded and soon returned to normallevels. Total WBCs also reached a nadir on day 8, but returned to normallevels. Dose dependent decrease in the hematopoietic bone marrowcellularity is shown in FIG. 14. The FIG. shows cellularity in bonemarrow 6 days post initial injection of SNS-595 at various doses.

FIG. 15 shows neutrophil counts from blood samples on days 4, 6, 8, and12 post initial injection. As seen in FIG. 16, all SNS-595 dose groupsdemonstrated a significant decrease in peripheral neutrophils by day 8.As seen in FIG. 17, animals receiving 20 mg/kg injections of SNS-595 hadless than 50 cells/ml on day 8.

FIG. 18 shows that there is a minor platelet response at day 8 toSNS-595 injection. FIG. 19 shows percent change in body weight atvarious times after administering SNS-595. FIG. 20 shows bone marrowrebound at day 12 post injection of 20 mg/kg SNS-595.

Example 11 Clinical Trial Data of SNS-595 in Patients with HematologicMalignancies

SNS-595 was administered to patients with advanced or refractory acuteleukemias as a slow IV push. Diagnoses included AML (19 patients) andALL (2 patients). All patients had disease refractory to or relapsedfrom prior therapy (median 3 prior regimens (range 1-6)).

A total of 21 patients (9 female and 12 male; median age=64 yrs, range21-80) were treated in five cohorts using two schedules. In the firstschedule (A), a weekly dose of SNS-595 was administered for three weeksfollowed by 7 days off (qwk×3). In the second schedule (B), a dose ofSNS-595 was administered twice a week for two weeks (biwk×2). The cycleduration, including days off, was 28 days for both schedules. Schedule Ahad a total of 3 doses per cycle, and schedule B had a total of 4 dosesper cycle. Additional cycles were permitted if patients achieved stabledisease or better. The starting dose was 18 mg/m² on schedule A and 9mg/m² on schedule B, and dosage was escalated by cohort. Cohorts of 3-6patients were accrued to doses using a modified Fibonacci sequence.

Pharmacokinetic analyses for SNS-595 were performed on plasma samplescollected during cycle 1. Table 15 provides certain pharmacokineticparameters derived from the study.

TABLE 15 Pharmacokinetic Parameters Dose AUC_(inf) Cl_(obs) V_(ssobs)(mg/m²) Schedule T ½ hr μg · hr/ml L/hrm² L/m² 18 qwk x3 24 ± 4 8.0 ±1.4 2.3 ± 0.4 72 ± 21 27 qwk x3  22 ± 10 17.8 ± 5   1.6 ± 0.4 47 ± 21 9* biwk x2 24 ± 5 4.3 ± 1.3 2.3 ± 0.7 65 ± 2    13.5* biwk x2 21 ± 75.9 ± 2.9 2.5 ± 1.2 61 ± 6  *Similar PK after Days 4, 8, and 11administration.

Plasma SNS-595 concentrations were determined using a validated LC-MS/MSassay. Plasma exposures at the first two dose levels for each scheduleincreased linearly, resulting in AUCs of 4.3-17.8 μghr/mL for 9-27 mg/m²doses. CL, Vss and terminal half-lives were similar to those in solidtumor patients, and averaged ˜2 L/hr/m², 58 L/m², and 23 hr,respectively. Six patients distributed across all dosing groups shown inTable 15 experienced greater than 50% reductions in peripheral blastsfollowing cycle 1.

No dose limiting toxicities (DLTs) have been observed up to 27 mg/m² onthe qwk×3 schedule or up to 13.5 mg/m² on the biwk×2 schedule. Non-doselimiting toxicities included nausea/vomiting, diarrhea, and mucositis.Grade 4 neutropenic fever was observed in only one patient.

Other patient cohorts were administered dosages of 38 mg/m² and 50mg/m², respectively, according to Schedule A (qwk×3). Still otherpatient cohorts were administered dosages of 19 mg/m² and 25 mg/m²,respectively, according to Schedule B (biwk×2). Safety data are shown inTable 16.

TABLE 16 Serious Adverse Events (SAE) Possibly Related to Study DrugEvent Name 1 patient for each CTCAE v3.0 Grade of the following qwk x3biwk x2 Pneumonia with Grade 3 not Neutropenia observed Infection withGrade 3 not Neutropenia observed Neutropenic not Grade 4 Fevers observedInfection not Grade 3 observed

Useful dosing schedules for treatment of hematologic malignancies caninclude from about 50 mg/m² to about 80 mg/m² administered once a weekfor three weeks, Another dose finding use in treatment of hematologicmalignancies is about 55 mg/m² to about 75 mg/m² administered once aweek for three weeks. Other doses doses finding use in treatment ofhematologic malignancies include 60, 65, 70 or 75 mg/m² administeredonce a week for three weeks.

Other dosing schedules useful for treatment of patients with hematologicmalignacies can include about 25 mg/m² to about 50 mg/m² administeredtwice a week for two weeks. Another dose finding use in treatment ofhematologic malignancies is about 30 mg/m² to about 45 mg/m²administered twice a week for two weeks. Other doses finding use intreatment of hematologic malignancies include 30, 35, 40, or 45 mg/m²administered twice a week for two weeks.

The embodiments of the invention described above are intended to bemerely exemplary, and those skilled in the art will recognize, or willbe able to ascertain using no more than routine experimentation,numerous equivalents of specific compounds, materials, and procedures.All such equivalents are considered to be within the scope of theinvention and are encompassed by the appended claims.

1-51. (canceled)
 52. A method of treating leukemia, comprisingadministering to a human from about 50 to about 100 mg/m² of anenantiomerically pure(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid, wherein the leukemia is a chronic lymphocytic leukemia, chronicmyelocytic leukemia, acute lymphoblastic leukemia or acute myelogenousleukemia.
 53. A method of treating acute myelogenous leukemia comprisingadministering a dose of about 50 mg/m² to about 100 mg/m² of(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid and a therapeutically effective dose of a second agent to a humanhaving acute myelogenous leukemia.
 54. The method of claim 53, whereinthe acute myelogenous leukemia is a myeloblastic leukemia orpromyelocytic leukemia.
 55. The method of claim 53, wherein the leukemiais relapsed, refractory or resistant to therapy selected from surgery,chemotherapy, radiation therapy, hormonal therapy, biological therapy,immunotherapy, blood transfusions, and combinations thereof.
 56. Themethod of claim 53, wherein the dose of(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid is from 50 mg/m² to 90 mg/m².
 57. The method of claim 53, whereinthe dose of(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid is from 80 mg/m² to 90 mg/m².
 58. The method of claim 53, whereinthe dose of(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid is from 85 mg/m² to 95 mg/m².
 59. The method of claim 53, whereinthe dose of(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid is from 90 mg/m² to 100 mg/m².
 60. The method of claim 53, wherein(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid is administered as an IV injection.
 61. The method of claim 53,wherein(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid is administered in an IV push of 10-15 minutes duration.
 62. Themethod of claim 53, wherein the second agent is selected from the groupconsisting of an alkylating agent, an anti-neoplastic agent, ananti-metabolite, a platinum coordination complex, a topoisomerase IIinhibitor, and radiation.
 63. The method of claim 62, wherein theanti-metabolite is selected from the group consisting of a folateanalog, purine analog, adenosine analog, pyrimidine analog, andsubstituted urea.
 64. The method of claim 62, wherein the second agentis selected from the group consisting of azacitidine, decitabine,busulfan, chlorambucil, cyclophosphamide, melphalan, carmustine,bleomycin, dactinomycin, daunorubicin, daunorubicin hydrochloride,doxorubicin, doxorubicin hydrochloride, methotrexate, pemetrexed,mercaptopurine, thioguanidine, cladribine, pentostatin, cytarabine,capecitabine, fluorouracil, hydroxyurea, carboplatin, cisplatin,oxaliplatin, etoposide, teniposide, and vincristine sulfate.
 65. Themethod of claim 62, wherein the second agent is selected from the groupconsisting of azacitidine, decitabine, cyclophosphamide, daunorubicin,daunorubicin hydrochloride, doxorubicin, doxorubicin hydrochloride,cytarabine, etoposide, and vincristine sulfate.